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Renin-Angiotensin Aldosterone System Modulation and Cardiovascular-Kidney-Metabolic Health

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28 June 2024

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28 June 2024

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Abstract
Similar to humans, the renin-angiotensin-aldosterone system (RAAS) plays a key role in regulating blood pressure and body fluid homeostasis in dogs and cats. The classical RAAS pathway, which involves the conversion of angiotensin I to angiotensin II by the angiotensin converting enzyme (ACE), leads to aldosterone production and associated maladaptive effects in cardiovascular and renal diseases. Recent studies have highlighted the alternative RAAS pathway, which counteracts these effects through angiotensin 1-7, promoting vasodilation and reducing inflammation. Beyond RAAS modulation, RAAS inhibitors have been shown to exert significant anti-inflammatory properties. This is particularly relevant given the American Heart Association's recent focus on Cardiovascular-Kidney-Metabolic (CKM) health, which emphasizes the interconnected risks of cardiovascular disease, chronic kidney disease (CKD), type 2 diabetes, and obesity. These conditions share common pathophysiological pathways, including chronic inflammation, oxidative stress, and metabolic dysregulation. Advances in biomedical research, including the development of adult stem cell-derived canine organoids, provide impetus to study the effects of RAAS modulators and new CVD drugs on CKM health, with a focus on epithelial inflammation within the context of One Health.
Keywords: 
Subject: Medicine and Pharmacology  -   Veterinary Medicine

What We Know about the Renin-Angiotensin Aldosterone System in Dogs and Cats 

The renin-angiotensin-aldosterone system (RAAS is integral to regulating blood pressure (BP) and fluid balance (Hall et al., 1989). The classical RAAS pathway refers to the peptide cascade involving the conversion of angiotensin I (ANG I) to angiotensin II (ANG II) by angiotensin-converting enzyme (ACE), eventually leading to increased adrenal production of aldosterone (ALD). Physiological consequences of ANG II and ALD include vasoconstriction, sodium and water retention, and myocardial and vascular fibrosis, which are considered maladaptive in the context of cardiovascular and renal diseases (Young et al., 1994; Shiffrin, 2006; Waanders et al., 2011). In addition to the ANG II-ALD axis, it is now well-recognized that the RAAS also includes additional signaling pathways that balance the effects of the classical RAAS. Specifically, the alternative RAAS pathway involves the conversion of ANG II by the enzyme angiotensin-converting enzyme 2 (ACE2) into angiotensin 1-7 (Ang 1-7), with downstream signaling leading to vasodilation, diuresis, natriuresis, and mitigation of vascular inflammation (Esteban et al., 2009). Therefore, the alternative RAAS pathway provides an internal counterregulatory mechanism that can partly mitigate the negative effects of ANG II and ALD. In theory, the ideal RAAS-modulating therapy would downregulate the classical RAAS and upregulate the alternative RAAS pathway (Arendse et al., 2019).
There is scarce information about the activation of the RAAS in dogs with congestive heart failure (CHF), independent of treatment. However, multiple clinical trials have demonstrated a clinical benefit of RAAS modulators, such as ACE inhibitors (The COVE Study Group, 1995; The IMPROVE Study Group, 1995; BENCH, 1999; Besche et al., 2007), or mineralocorticoid receptor antagonists (MRA) (Coffman et al., 2021) in dogs with cardiac diseases. A recent retrospective study by Ward et al. (2021) also showed that administering a higher dose of an ACE inhibitor was linked to improved survival rates in dogs with initial onset of CHF. Furthermore, among the canine subgroup with CHF during the ACE inhibitor prescription, a higher dose was linked to better chances of survival at two years. In addition, the physiology of the RAAS and its response to RAAS inhibition has been extensively studied in experimental models of RAAS activation by our group (Mochel et al., 2013a, b; 2014, 2015, 2019; Mochel & Danhof, 2015; Sotillo et al., 2023; Schneider et al., 2023).
In cats with systemic hypertension (SHT), the activation of RAAS components can vary:
  • Plasma renin activity (PRA). Jepson et al. (2014) reported low PRA levels in cats with SHT, while a previous retrospective study from our consortium found elevated PRA levels in SHT cats given amlodipine, but no differences in PRA in untreated SHT patients compared to healthy controls (Ward et al., 2022).
  • Angiotensins I and II. Similarly, our 2022 retrospective study found a significant elevation in ANG I (but not ANG II) levels in cats with SHT who were treated with amlodipine, but no differences were found in untreated SHT patients compared to healthy controls.
  • Aldosterone. Jepson et al. (2014) reported elevated ALD levels in cats with SHT. Consistent with our findings on PRA and ANG I, elevation in ALD was only observed in SHT cats treated with amlodipine in our 2022 retrospective study.
These changes in RAAS due to amlodipine were later confirmed in a prospective study, which included 20 healthy cats treated with AML besylate (0.625 mg PO q24h) for 14 days. The study showed increases in ANG I, ANG II, and PRA compared to the placebo, but no significant changes were seen in ALD (Garcia Marrero et al., 2024). Both studies (Ward et al., 2022; Garcia Marrero et al., 2024) also reported an increase in Ang 1-7, which could potentially be associated with positive clinical outcomes in feline patients with SHT.
In cats with cardiomyopathy, data from our retrospective study (Ward et al., 2022) showed consistent increases in PRA, ANG I and ALD compared with healthy cats, and these differences remained significant after considering subgroups of untreated or furosemide-treated cats.
In cats with chronic kidney disease (CKD), a previous study by Mishina et al. (1998) reported a significant elevation in ANG II levels in seven cats with renal disease compared to the control group (N=11). However, the study had several limitations, including a lack of methodological information and a small sample size. Additionally, the study lacked information on the cats systolic BP, and a clear definition for the “normal” (control) group.
More recently, Lourenço et al. (2022) showed that intrarenal levels of ANG I were consistently elevated in cats with CKD, while ANG II levels were not. This could imply a differential regulation of RAAS components within the kidney compared to the systemic circulation.
For a comprehensive overview of the RAAS and its suppression in dogs and cats, please refer to the excellent review by Ames et al. (2018).

RAAS Activation, Vascular Inflammation and Remodeling: Lessons from Experimental Models and Human Studies 

Excessive activation of the RAAS plays a crucial role in vascular inflammation and remodeling. This is particularly relevant as the American Heart Association (AHA) has recently issued a comprehensive Presidential Advisory highlighting the intricate connections between cardiovascular diseases (CVD), CKD, type 2 diabetes (T2DM), and obesity (Ndumele et al., 2023). This integrated approach aims to redefine how these conditions are understood and managed, introducing the concept of Cardiovascular-Kidney-Metabolic (CKM) health which outlines the overlapping and mutually reinforcing risks of CVD, CKD, T2DM, and obesity. Among others, these diseases share common pathophysiological pathways, including inflammation, oxidative stress, and metabolic dysregulation, which exacerbate disease progression and complicate their therapeutic management overall.
Significant findings from the scientific literature on the role of RAAS activation in cardiovascular remodeling include, among others:
  • Pro-inflammatory actions of angiotensin II. ANG II regulates the expression of cytokines and chemokines in the kidneys, vessels, and heart, contributing to vascular inflammation and remodeling (Pacurari et al., 2014; Hahn et al., 1995; Tummala et al., 1999). Chronic infusion of ANG II is associated with increased BP, myocardial infiltration of inflammatory cells, and cardiac fibrosis (Qi et al., 2011).
  • Oxidative stress and end-organ damage. ANG II-induced oxidative stress and mechanical injury from elevated BP result in end-organ damage, manifested by myocardial infarction, congestive heart failure (CHF), and CKD (Devonald & Karet, 2002; Chobanian et al., 2003).
This body of evidence explains why the classical pathway has historically been the primary focus of RAAS-mitigating drug therapy in both human and veterinary medicine. RAAS inhibitors, such as ACE inhibitors and angiotensin receptor blockers (ARBs) have been shown to significantly reduce levels of various pro-inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukins like IL-6 and IL-1β (Krysiak & Okopień 2011, 2012; Fernandez et al., 2008). These reductions in inflammatory markers contribute to the protective effects of RAAS inhibitors on cardiovascular and renal health. In particular, RAAS inhibitors reduce oxidative stress by decreasing the production of reactive oxygen species (ROS), thus preserving endothelial function and preventing vascular damage (Gainer et al., 1998). The anti-inflammatory effects of these inhibitors are mediated through the blockade of ANG II, which promotes inflammation and oxidative stress, and modulation of key signaling pathways such as NF-κB, which plays a critical role in the inflammatory response. Clinically, these effects translate to reduced cardiovascular morbidity and mortality, particularly benefiting patients with chronic inflammatory conditions such as heart failure, hypertension, and kidney disease. Additionally, the reduction in inflammatory markers associated with RAAS inhibitors improves outcomes in patients with metabolic syndrome and diabetes (Vaccari et al., 2008; Bähr et al., 2011).
A systematic review and meta-analysis of 32 randomized controlled trials consistently support these findings, underscoring the comprehensive benefits of RAAS inhibitors not only in blood pressure control but also in reducing systemic inflammation and protecting cardiovascular and renal function (Awad et al., 2022). This meta-analysis, which included 3,403 patients, found that ACE inhibitors significantly reduce inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-α. Specifically, ACE inhibitors such as perindopril and ramipril showed substantial reductions in IL-6, while enalapril reduced TNF-α and CRP. ARBs, however, showed a significant reduction in IL-6, but not consistently in other markers. These findings suggest that ACE inhibitors are more effective than ARBs in lowering systemic inflammation, highlighting their potential benefits in cardiovascular disease prevention and management.
A study published in the European Heart Journal (Cleland et al., 2021) recently reported the anti-inflammatory and anti-fibrotic effects of the MRA spironolactone in patients with heart failure. The study revealed that spironolactone significantly reduces pro-inflammatory cytokines such as TNF-α and IL-6, leading to decreased inflammation and fibrosis. This reduction also suppresses collagen type 1 synthesis, a key component of cardiac fibrosis. The study observed improved cardiac function, including enhanced left ventricular ejection fraction, and reduced ventricular remodeling. Clinically, spironolactone treatment was associated with fewer hospitalizations for heart failure exacerbations. These findings highlight the role of spironolactone in managing fluid retention, reducing inflammation, and limiting fibrosis, ultimately improving overall cardiac outcomes in heart failure patients.
Another mechanistic study published in Clinical and Experimental Immunology explored the anti-inflammatory and anti-fibrotic effects of spironolactone on ex vivo-activated human blood leukocytes through gene expression analysis and enzyme immunoassay (Bendtzen et al., 2003). This study focused on pro- and anti-inflammatory cytokines. Results showed a significant suppression of pro-inflammatory cytokine transcription and secretion, including TNF-α, lymphotoxin, IFN-γ, GM-CSF, and IL-6 (70–90% inhibition).
Finally, a study conducted by Kato et al. (2014) in RAW 264.7 macrophage-like cells and mouse peritoneal macrophages showed that spironolactone significantly inhibits the production of TNF-α and prostaglandin E2 induced by LPS. Overall, these results suggest that spironolactone would inhibit proinflammatory mediators induced by LPS through the inactivation of IκB kinase (IKK)/nuclear factor (NF)-κB.

Cardiovascular-Kidney Metabolic Health beyond the RAAS: Recent Progress in the Therapeutic Management of Cardiorenal Diseases 

Accumulating data from several large, placebo-controlled studies suggests that sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists offer therapeutic benefits in the management of cardiovascular diseases, regardless of the patient's diabetic status (Zinman et al., 2015; Neal et al., 2017; Persson et al., 2018; Birkeland et al., 2019; McMurray et al., 2019; Inzucchi et al., 2020; Packer et al., 2020; Butler et al., 2021; Kosiborod et al., 2023).
In addition to their effects on glucose excretion, SGLT-2 inhibitors also have a positive impact on systemic metabolism by reducing systemic inflammation and oxidative stress, shifting metabolism towards ketone body production (Bertoccini and Baroni, 2021), promoting autophagy, and suppressing glycation end-product signaling. The SGLT-2 inhibitor dapagliflozin has been shown to have anti-inflammatory effects by inhibiting the overexpression of LPS-induced TLR-4 and activating NF-κB in human endothelial cells and differentiated macrophages (Abdollahi et al., 2022). In both human umbilical vein endothelial cells and macrophages, dapagliflozin significantly reduced the overexpression of TLR-4 under normal glucose and high glucose conditions. Furthermore, dapagliflozin shifted the balance from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages (Abdollahi et al., 2022).
GLP-1 receptor (GLP1R) agonists are promising therapeutic agents due to their potent anti-inflammatory properties and diverse clinical implications. They regulate immune cell signaling, decrease activation of the NF-κB pathway, and lower levels of pro-inflammatory cytokines (Krasner et al., 2014; Wei et al., 2016). This modulatory effect leads to a decrease in systemic inflammation and an improvement in disease outcomes (Alharbi et al., 2024).
A study published by Cordeanu et al. (2023) in the European Heart Journal demonstrated a correlation between human cardiac GLP1R expression levels and low-grade inflammation and endothelial dysfunction. The study found that increased GLP1R expression leads to higher levels of oxidative stress, which can be reduced by GLP-1 receptor agonists through a canonical GLP1R AMPK-mediated pathway. Therefore, the cardiovascular benefits of GLP1RA may be attributed to their antioxidant and anti-inflammatory properties, particularly within the cardiac system.
A recent Phase IIIb clinical trial involving 3,533 patients with T2DM and CKD showed that patients who received the GLP1R agonist semaglutide were 24% less likely to experience "major kidney disease events", such as kidney failure or death due to kidney complications, compared to those who received a placebo (Perkovic et al., 2024; NCT03819153). Participants who received semaglutide were also 29% less likely to die from heart attacks and other major cardiovascular incidents than those who received a placebo, and 20% less likely to die from any cause during the trial period. The trial also showed that semaglutide may slow the deterioration of a person's kidneys. At 104 weeks, the urinary albumin-to-creatinine ratio was lowered by 12% in the placebo group, compared to 40% in the semaglutide group. Loss of kidney function, as indicated by the cystatin C-based eGFR, was lower by 3.39 mL per minute per 1.73 m2 in the semaglutide group compared to placebo at that time. Based on experimental models and biomarker data, GLP1R agonists may have direct effects on the kidney, including reducing inflammation, oxidative stress, and fibrosis. The GLP1R is present in both the kidney (although moderately expressed) and immune cells. GLP1R agonists have been shown to decrease the expression of proinflammatory and profibrotic mediators in these cells (Alicic et al., 2021; Dalbøge et al., 2022; Tuttle et al., 2023; Alicic et al., 2023).

Establishing Relevant In Vitro Models to Study Anti-Inflammatory Effects of Therapeutic Drugs that Modulate Cardiovascular and Kidney Metabolic Health 

Conventional rodent models, such as mice, have been extensively used in studying human diseases due to their cost effectiveness, ethical considerations, and easy access to genetically engineered technology. However, despite the widespread use of murine models in biomedical research, the translational value of such studies remains limited because they often fail to accurately mimic human diseases (Jacob, 2016). A study by Seok et al. (2013), published in the Proceedings of the National Academy of Sciences, showed that mouse models poorly replicate inflammatory responses from different etiologies in humans. Among the genes that were significantly changed in humans, the murine orthologs had a very poor correlation (e.g., R2 between 0.0 and 0.1) with their human counterparts.
Additionally, given the high failure rate of drugs during discovery and development, there is a critical need for more accurate animal models for preclinical studies (Waring et al., 2015). This need is highlighted by the recent passing of the FDA Modernization Act 2.0, which restricts the use of non-informative animal models, such as rodents, in testing experimental drugs before they can be evaluated in clinical trials (Zushin et al., 2023). This new act allows drug sponsors to use scientifically rigorous and proven non-model animal testing methods or replacement tests that are more suitable than animal testing.
As a result, there is now an incentive to use more relevant animal models, such as dogs, which are typically more representative for chronic disease modeling than rodents. This is because dogs have a relatively large body size, longer lifespan, physiological similarities to humans, and a tendency to develop spontaneous and clinical analogues of human diseases, such as cardiorenal and metabolic diseases, or other inflammatory and neurodegenerative diseases (Gordon et al., 2009; Gilmore & Greer, 2015; Jacob, 2016; Kaeberlein et al., 2016; Masters et al., 2018; Sebbag et al., 2018a,b, 2019, Sebbag & Mochel, 2020; Kopper et al., 2021).
Recent advances in biomedical research have led to the development of adult stem cells in three-dimensional culture systems, which enable ex vivo epithelial growth into organoids (Ootani et al., 2009, Sato et al., 2009). These stem cell-derived organoids offer several advantages over conventional two-dimensional epithelial systems, which utilize cancer-derived cell lines such as Caco-2, T84, and HT29 (Sun et al., 2004; Mochel et al., 2017), or spontaneously immortalized epithelial cells like rat intestinal epithelial cultures. These traditional methods can often fail to accurately reproduce the structure and function of the in vivo epithelium. In contrast, the 3D organoid culture method excels by better harnessing innate endogenous cellular programming within higher-order tissue organization (Foulke-Abel et al., 2014; Loewa et al., 2023).
Our laboratory has recently established an in vitro model using adult stem-cell derived organoids (Gabriel et al., 2022) stimulated by canine-specific TNF-α to study epithelial inflammation and drug response in dogs (Barko et al., 2024; Zdyrski et al., 2024). 3D organoids were dissociated and placed onto Transwell inserts to mimic cellular polarity. The 2D monolayers reached full coverage in about 8 days, with TEER values rising from around 19 Ω.cm² on Day 3 to about 2,809 Ω.cm² on Day 9. On the experiment day, 5 ng/mL of canine TNF-α was added to the basolateral chamber 4 hours after measuring TEER values and incubated for another 6 hours. This resulted in a significant decrease in TEER compared to pre-treatment levels. TNF-α also caused a significant increase in IL-8 secretion in both the apical and basolateral supernatants. RNA-sequencing showed that TNF-α treatment significantly upregulated various inflammatory cytokines and barrier function regulators (e.g., IL-7, IL-8, CXCL10, IL-17C, CCL20, IL-23A, ROCK1, ROCK2) in the canine colonoids.
Another recent study published by our laboratory (Sahoo et al., 2022) showed that LPS plays a significant role in promoting cancer progression by modulating gene expression and proliferation of intestinal epithelial cells in dogs with gastrointestinal diseases, such as inflammatory bowel disease (IBD) and intestinal mast cell tumors. The study concluded that LPS incubation leads to a pro-cancer gene expression profile and increased proliferation in IBD enteroids and colonoids. This study emphasized the significance of the crosstalk between the LPS/TLR-4 signaling pathway and various metabolic pathways, such as primary bile acid biosynthesis and secretion, the peroxisome, the renin-angiotensin system, glutathione metabolism, and arachidonic acid pathways. These interactions are critical in driving chronic inflammation and carcinogenesis.

References

  1. Abdollahi E, Keyhanfar F, Delbandi AA, Falak R, Hajimiresmaiel SJ, Shafiei M. Dapagliflozin exerts anti-inflammatory effects via inhibition of LPS-induced TLR-4 overexpression and NF-κB activation in human endothelial cells and differentiated macrophages. Eur J Pharmacol. 2022 Mar 5;918:174715. Epub 2022 Jan 11. PMID: 35026193.
  2. Alharbi SH. Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications. Ther Adv Endocrinol Metab. 2024 Jan 27;15:20420188231222367. PMID: 38288136; PMCID: PMC10823863.
  3. Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol. 2021 Apr;17(4):227-244. Epub 2020 Nov 20. PMID: 33219281.
  4. Alicic RZ, Neumiller JJ, Tuttle KR. Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease. Curr Opin Nephrol Hypertens. 2023 Jul 1;32(4):377-385. Epub 2023 May 4. PMID: 37195250; PMCID: PMC10241427.
  5. Ames MK, Atkins CE, Pitt B. The renin-angiotensin-aldosterone system and its suppression. J Vet Intern Med. 2019 Mar;33(2):363-382. https://doi.org/10.1111/jvim.15454. Epub 2019 Feb 26. Erratum in: J Vet Intern Med. 2019 Sep;33(5):2551. PMID: 30806496; PMCID: PMC6430926. [CrossRef]
  6. Arendse LB, Danser AHJ, Poglitsch M, Touyz RM, Burnett JC Jr, Llorens-Cortes C, Ehlers MR, Sturrock ED. Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure. Pharmacol Rev. 2019 Oct;71(4):539-570. PMID: 31537750; PMCID: PMC6782023. [CrossRef]
  7. Awad K, Zaki MM, Mohammed M, Lewek J, Lavie CJ, Banach M; Lipid and Blood Pressure Meta-analysis Collaboration Group. Effect of the Renin-Angiotensin System Inhibitors on Inflammatory Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Mayo Clin Proc. 2022 Oct;97(10):1808-1823. PMID: 36202494. [CrossRef]
  8. Bähr IN, Tretter P, Krüger J, Stark RG, Schimkus J, Unger T, Kappert K, Scholze J, Parhofer KG, Kintscher U. High-dose treatment with telmisartan induces monocytic peroxisome proliferator-activated receptor-γ target genes in patients with the metabolic syndrome. Hypertension. 2011 Oct;58(4):725-32. Epub 2011 Aug 29. PMID: 21876071. [CrossRef]
  9. Barko P, Zdyrski C, Ralston A, Feauto R, Allenspach K, Mochel JP, Williams DA. Microbial Indole Catabolites of Tryptophan Regulate Mucosal Barrier Function and Inflammatory Responses in Canine Colonoids. American College of Veterinary Internal Medicine 2024 Forum, Minneapolis (MS).
  10. BENCH (BENazepril in Canine Heart disease) Study Group. The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: Results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial. J Vet Cardiol. 1999 May;1(1):7-18. PMID: 19081317. [CrossRef]
  11. Bendtzen K, Hansen PR, Rieneck K; Spironolactone/Arthritis Study Group. Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis. Clin Exp Immunol. 2003 Oct;134(1):151-8. PMID: 12974768; PMCID: PMC1808828. [CrossRef]
  12. Bertoccini L, Baroni MG. GLP-1 Receptor Agonists and SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: New Insights and Opportunities for Cardiovascular Protection. Adv Exp Med Biol. 2021;1307:193-212. PMID: 32034729.
  13. Besche B, Chetboul V, Lachaud Lefay MP, Grandemange E. Clinical evaluation of imidapril in congestive heart failure in dogs: results of the EFFIC study. J Small Anim Pract. 2007 May;48(5):265-70. PMID: 17472664. [CrossRef]
  14. Birkeland KI, Bodegard J, Norhammar A, Kuiper JG, Georgiado E, Beekman-Hendriks WL, Thuresson M, Pignot M, Herings RMC, Kooy A. How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT-2 inhibitors? A large European observational study. Diabetes Obes Metab. 2019 Apr;21(4):968-974. PMID: 30537226; PMCID: PMC6590461.
  15. Butler J, Anker SD, Filippatos G, Khan MS, Ferreira JP, Pocock SJ, Giannetti N, Januzzi JL, Piña IL, Lam CSP, Ponikowski P, Sattar N, Verma S, Brueckmann M, Jamal W, Vedin O, Peil B, Zeller C, Zannad F, Packer M; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021 Mar 31;42(13):1203-1212. PMID: 33420498; PMCID: PMC8014525.
  16. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003 Dec;42(6):1206-52. Epub 2003 Dec 1. PMID: 14656957. [CrossRef]
  17. Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, Cuthbert J, Verdonschot JAJ, Petutschnigg J, Ahmed FZ, Cosmi F, Brunner La Rocca HP, Mamas MA, Clark AL, Edelmann F, Pieske B, Khan J, McDonald K, Rouet P, Staessen JA, Mujaj B, González A, Diez J, Hazebroek M, Heymans S, Latini R, Grojean S, Pizard A, Girerd N, Rossignol P, Collier TJ, Zannad F; HOMAGE Trial Committees and Investigators. The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart 'OMics' in AGEing (HOMAGE) randomized clinical trial. Eur Heart J. 2021 Feb 11;42(6):684-696. PMID: 33215209; PMCID: PMC7878013. [CrossRef]
  18. Coffman M, Guillot E, Blondel T, Garelli-Paar C, Feng S, Heartsill S, Atkins CE. Clinical efficacy of a benazepril and spironolactone combination in dogs with congestive heart failure due to myxomatous mitral valve disease: The BEnazepril Spironolactone STudy (BESST). J Vet Intern Med. 2021 Jul;35(4):1673-1687. Epub 2021 May 24. PMID: 34028078; PMCID: PMC8295662. [CrossRef]
  19. Cordeanu EM, Qureshi AW, Mroueh A, Mazzucotelli JP, Schini-Kerth V. GLP1 receptor agonists exhibit antioxidant and anti-inflammatory properties in human heart tissue via the canonical GLP1 receptor expression through a AMPK-mediated pathway. Eur Heart J. 2023 Nov 44.
  20. Dalbøge LS, Christensen M, Madsen MR, Secher T, Endlich N, Drenic' V, Manresa-Arraut A, Hansen HH, Rune I, Fink LN, Østergaard MV. Nephroprotective Effects of Semaglutide as Mono- and Combination Treatment with Lisinopril in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease. Biomedicines. 2022 Jul 11;10(7):1661. PMID: 35884965; PMCID: PMC9313388. [CrossRef]
  21. Devonald MA, Karet FE. Targeting the renin-angiotensin system in patients with renal disease. J R Soc Med. 2002 Aug;95(8):391-7. PMID: 12151488; PMCID: PMC1279963. [CrossRef]
  22. Esteban V, Heringer-Walther S, Sterner-Kock A, de Bruin R, van den Engel S, Wang Y, Mezzano S, Egido J, Schultheiss HP, Ruiz-Ortega M, Walther T. Angiotensin-(1-7) and the g protein-coupled receptor MAS are key players in renal inflammation. PLoS One. 2009;4(4):e5406. Epub 2009 Apr 30. PMID: 19404405; PMCID: PMC2672164. [CrossRef]
  23. Fernandez M, Triplitt C, Wajcberg E, Sriwijilkamol AA, Musi N, Cusi K, DeFronzo R, Cersosimo E. Addition of pioglitazone and ramipril to intensive insulin therapy in type 2 diabetic patients improves vascular dysfunction by different mechanisms. Diabetes Care. 2008 Jan;31(1):121-7. Epub 2007 Oct 1. PMID: 17909084. [CrossRef]
  24. Foulke-Abel J, In J, Kovbasnjuk O, Zachos NC, Ettayebi K, Blutt SE, Hyser JM, Zeng XL, Crawford SE, Broughman JR, Estes MK, Donowitz M. Human enteroids as an ex-vivo model of host-pathogen interactions in the gastrointestinal tract. Exp Biol Med (Maywood). 2014 Sep;239(9):1124-34. Epub 2014 Apr 9. PMID: 24719375; PMCID: PMC4380516. [CrossRef]
  25. Gabriel V, Zdyrski C, Sahoo DK, Dao K, Bourgois-Mochel A, Kopper J, Zeng XL, Estes MK, Mochel JP, Allenspach K. Standardization and Maintenance of 3D Canine Hepatic and Intestinal Organoid Cultures for Use in Biomedical Research. J Vis Exp. 2022 Jan 31;(179). PMID: 35156656. [CrossRef]
  26. Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998 Oct 29;339(18):1285-92. PMID: 9791144. [CrossRef]
  27. Garcia Marrero TM, Ward JL, Tropf MA, Bourgois-Mochel A, Guillot E, Domenig O, Yuan L, Kundu D, Mochel JP. Effect of amlodipine on the circulating renin-angiotensin-aldosterone system in healthy cats. J Vet Intern Med. 2024 Mar-Apr;38(2):913-921. PMID: 38334012; PMCID: PMC10937479. Epub 2024 Feb 9. [CrossRef]
  28. Gilmore KM, Greer KA. Why is the dog an ideal model for aging research? Exp Gerontol. 2015 Nov;71:14-20. Epub 2015 Aug 29. PMID: 26325590. [CrossRef]
  29. Gordon I, Paoloni M, Mazcko C, Khanna C. The Comparative Oncology Trials Consortium: using spontaneously occurring cancers in dogs to inform the cancer drug development pathway. PLoS Med. 2009 Oct;6(10):e1000161. Epub 2009 Oct 13. PMID: 19823573; PMCID: PMC2753665. [CrossRef]
  30. Jacob JA. Researchers Turn to Canine Clinical Trials to Advance Cancer Therapies. JAMA. 2016 Apr 19;315(15):1550-2. PMID: 27027696. [CrossRef]
  31. Kaeberlein M, Creevy KE, Promislow DE. The dog aging project: translational geroscience in companion animals. Mamm Genome. 2016 Aug;27(7-8):279-88. Epub 2016 May 3. PMID: 27143112; PMCID: PMC4936929. [CrossRef]
  32. Kopper JJ, Iennarella-Servantez C, Jergens AE, Sahoo DK, Guillot E, Bourgois-Mochel A, Martinez MN, Allenspach K, Mochel JP. Harnessing the Biology of Canine Intestinal Organoids to Heighten Understanding of Inflammatory Bowel Disease Pathogenesis and Accelerate Drug Discovery: A One Health Approach. Front Toxicol. 2021 Nov 10;3:773953. PMID: 35295115; PMCID: PMC8915821. [CrossRef]
  33. Krysiak R, Okopień B. Lymphocyte-suppressing action of angiotensin-converting enzyme inhibitors in coronary artery disease patients with normal blood pressure. Pharmacol Rep. 2011;63(5):1151-61. PMID: 22180357. [CrossRef]
  34. Krysiak R, Okopień B. Different effects of perindopril and enalapril on monocyte cytokine release in coronary artery disease patients with normal blood pressure. Pharmacol Rep. 2012;64(6):1466-75. PMID: 23406757. [CrossRef]
  35. Jepson RE, Syme HM, Elliott J. Plasma renin activity and aldosterone concentrations in hypertensive cats with and without azotemia and in response to treatment with amlodipine besylate. J Vet Intern Med. 2014 Jan-Feb;28(1):144-53. Epub 2013 Nov 13. PMID: 24428319; PMCID: PMC4895535. [CrossRef]
  36. Hall JE, Coleman TG, Guyton AC. The renin-angiotensin system. Normal physiology and changes in older hypertensives. J Am Geriatr Soc. 1989 Aug;37(8):801-13. PMID: 2666488. [CrossRef]
  37. Inzucchi SE, Fitchett D, Jurišić-Eržen D, Woo V, Hantel S, Janista C, Kaspers S, George JT, Zinman B; EMPA-REG OUTCOME® Investigators. Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose-lowering therapy? Diabetes Obes Metab. 2020 Apr;22(4):631-639. PMID: 31789445.
  38. Kato Y, Kamiya H, Koide N, Odkhuu E, Komatsu T, Dagvadorj J, Watarai A, Kondo M, Kato K, Nakamura J, Yokochi T. Spironolactone inhibits production of proinflammatory mediators in response to lipopolysaccharide via inactivation of nuclear factor-κB. Immunopharmacol Immunotoxicol. 2014 Jun;36(3):237-41. PMID: 24852317. [CrossRef]
  39. Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Møller DV, Shah SJ, Treppendahl MB, Verma S, Abhayaratna W, Ahmed FZ, Chopra V, Ezekowitz J, Fu M, Ito H, Lelonek M, Melenovsky V, Merkely B, Núñez J, Perna E, Schou M, Senni M, Sharma K, Van der Meer P, von Lewinski D, Wolf D, Petrie MC; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023 Sep 21;389(12):1069-1084. Epub 2023 Aug 25. PMID: 37622681.
  40. Krasner NM, Ido Y, Ruderman NB, Cacicedo JM. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One. 2014 May 16;9(5):e97554. PMID: 24835252; PMCID: PMC4023984.
  41. Loewa A, Feng JJ, Hedtrich S. Human disease models in drug development. Nat Rev Bioeng. 2023 May 11:1-15. Epub ahead of print. PMID: 37359774; PMCID: PMC10173243. [CrossRef]
  42. Lourenço BN, Coleman AE, Berghaus RD, Tarigo JL, Schmiedt CW, Brown SA. Characterization of the intrarenal renin-angiotensin system in cats with naturally occurring chronic kidney disease. J Vet Intern Med. 2022 Mar;36(2):647-655. Epub 2022 Jan 19. PMID: 35352404; PMCID: PMC8965263. [CrossRef]
  43. Masters AK, Berger DJ, Ware WA, Langenfeld NR, Coetzee JF, Mochel JPM, Ward JL. Effects of short-term anti-inflammatory glucocorticoid treatment on clinicopathologic, echocardiographic, and hemodynamic variables in systemically healthy dogs. Am J Vet Res. 2018 Apr;79(4):411-423. PMID: 29583045. [CrossRef]
  44. McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, Martinez FA, Bengtsson O, Ponikowski P, Sabatine MS, Sjöstrand M, Solomon SD; DAPA-HF Committees and Investigators. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail. 2019 Nov;21(11):1402-1411. Epub 2019 Jul 15. PMID: 31309699.
  45. Mishina M, Watanabe T, Fujii K, Maeda H, Wakao Y, Takahashi M. Non-invasive blood pressure measurements in cats: clinical significance of hypertension associated with chronic renal failure. J Vet Med Sci. 1998 Jul;60(7):805-8. PMID: 9713807. [CrossRef]
  46. Mochel JP, Peyrou M, Fink M, Strehlau G, Mohamed R, Giraudel JM, Ploeger B, Danhof M. Capturing the dynamics of systemic Renin-Angiotensin-Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs. J Vet Pharmacol Ther. 2013 Apr;36(2):174-80. Epub 2012 May 8. PMID: 22568394. [CrossRef]
  47. Mochel JP, Fink M, Peyrou M, Desevaux C, Deurinck M, Giraudel JM, Danhof M. Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology. Chronobiol Int. 2013 Nov;30(9):1144-59. Epub 2013 Aug 9. PMID: 23931032. [CrossRef]
  48. Mochel JP, Fink M, Bon C, Peyrou M, Bieth B, Desevaux C, Deurinck M, Giraudel JM, Danhof M. Influence of feeding schedules on the chronobiology of renin activity, urinary electrolytes and blood pressure in dogs. Chronobiol Int. 2014 Jun;31(5):715-30. Epub 2014 Mar 21. PMID: 24654920. [CrossRef]
  49. Mochel JP, Fink M, Peyrou M, Soubret A, Giraudel JM, Danhof M. Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs. Pharm Res. 2015 Jun;32(6):1931-46. Epub 2014 Dec 2. PMID: 25446774. [CrossRef]
  50. Mochel JP, Danhof M. Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned? Rev Physiol Biochem Pharmacol. 2015;169:43-69. PMID: 26428686. [CrossRef]
  51. Mochel JP, Teng CH, Peyrou M, Giraudel J, Danhof M, Rigel DF. Sacubitril/valsartan (LCZ696) significantly reduces aldosterone and increases cGMP circulating levels in a canine model of RAAS activation. Eur J Pharm Sci. 2019 Feb 1;128:103-111. Epub 2018 Nov 30. PMID: 30508581. [CrossRef]
  52. Mochel JP, Jergens AE, Kingsbury D, Kim HJ, Martín MG, Allenspach K. Intestinal Stem Cells to Advance Drug Development, Precision, and Regenerative Medicine: A Paradigm Shift in Translational Research. AAPS J. 2017 Dec 12;20(1):17. PMID: 29234895; PMCID: PMC6044282. [CrossRef]
  53. Mochel JP, Ward JL, Blondel T, Kundu D, Merodio MM, Zemirline C, Guillot E, Giebelhaus RT, de la Mata P, Iennarella-Servantez C, Blong A, Nam SL, Harynuk JJ, Suchodolski J, Tvarijonaviciute A, Cerón JJ, Bourgois-Mochel A, Zannad F, Sattar N, Allenspach K. Preclinical Modeling of Metabolic Syndrome to Study the Pleiotropic Effects of Novel Antidiabetic Therapy Independent of Obesity. 2024. Research Square. PMID: 37807924. [CrossRef]
  54. Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, Coresh J, Mathew RO, Baker-Smith CM, Carnethon MR, Despres JP, Ho JE, Joseph JJ, Kernan WN, Khera A, Kosiborod MN, Lekavich CL, Lewis EF, Lo KB, Ozkan B, Palaniappan LP, Patel SS, Pencina MJ, Powell-Wiley TM, Sperling LS, Virani SS, Wright JT, Rajgopal Singh R, Elkind MSV; American Heart Association. Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association. Circulation. 2023 Nov 14;148(20):1606-1635. https://doi.org/10.1161/CIR.0000000000001184. Epub 2023 Oct 9. Erratum in: Circulation. 2024 Mar 26;149(13):e1023. [CrossRef]
  55. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. Epub 2017 Jun 12. PMID: 28605608.
  56. Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H, Toda S, Sugihara H, Fujimoto K, Weissman IL, Capecchi MR, Kuo CJ. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med. 2009 Jun;15(6):701-6. Epub 2009 Apr 27. PMID: 19398967; PMCID: PMC2919216. [CrossRef]
  57. Packer M, Butler J, Filippatos G, Zannad F, Ferreira JP, Zeller C, Brueckmann M, Jamal W, Pocock SJ, Anker SD; EMPEROR Trial Committees and Investigators. Design of a prospective patient-level pooled analysis of two parallel trials of empagliflozin in patients with established heart failure. Eur J Heart Fail. 2020 Dec;22(12):2393-2398. Epub 2020 Dec 14. PMID: 33251659; PMCID: PMC7898542.
  58. Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, Baeres FMM, Idorn T, Bosch-Traberg H, Lausvig NL, Pratley R; FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024 May 24. Epub ahead of print. PMID: 38785209.
  59. Persson F, Nyström T, Jørgensen ME, Carstensen B, Gulseth HL, Thuresson M, Fenici P, Nathanson D, Eriksson JW, Norhammar A, Bodegard J, Birkeland KI. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study. Diabetes Obes Metab. 2018 Feb;20(2):344-351. Epub 2017 Sep 8. PMID: 28771923; PMCID: PMC5811811.
  60. Qi G, Jia L, Li Y, Bian Y, Cheng J, Li H, Xiao C, Du J. Angiotensin II infusion-induced inflammation, monocytic fibroblast precursor infiltration, and cardiac fibrosis are pressure dependent. Cardiovasc Toxicol. 2011 Jun;11(2):157-67. PMID: 21373977. [CrossRef]
  61. Sahoo DK, Borcherding DC, Chandra L, Jergens AE, Atherly T, Bourgois-Mochel A, Ellinwood NM, Snella E, Severin AJ, Martin M, Allenspach K, Mochel JP. Differential Transcriptomic Profiles Following Stimulation with Lipopolysaccharide in Intestinal Organoids from Dogs with Inflammatory Bowel Disease and Intestinal Mast Cell Tumor. Cancers (Basel). 2022 Jul 20;14(14):3525. PMID: 35884586; PMCID: PMC9322748.
  62. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009 May 14;459(7244):262-5. Epub 2009 Mar 29. PMID: 19329995. [CrossRef]
  63. Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006 Mar;47(3):312-8. Epub 2006 Jan 23. PMID: 16432039. [CrossRef]
  64. Schneider BK, Ward J, Sotillo S, Garelli-Paar C, Guillot E, Prikazsky M, Mochel JP. Breakthrough: a first-in-class virtual simulator for dose optimization of ACE inhibitors in translational cardiovascular medicine. Sci Rep. 2023 Feb 26;13(1):3300. PMID: 36843132; PMCID: PMC9968717. [CrossRef]
  65. Sebbag L, McDowell EM, Hepner PM, Mochel JP. Effect of tear collection on lacrimal total protein content in dogs and cats: a comparison between Schirmer strips and ophthalmic sponges. BMC Vet Res. 2018 Mar 1;14(1):61. PMID: 29490661; PMCID: PMC5831202. [CrossRef]
  66. Sebbag L, McDowell EM, Hepner PM, Mochel JP. Effect of tear collection on lacrimal total protein content in dogs and cats: a comparison between Schirmer strips and ophthalmic sponges. BMC Vet Res. 2018 Mar 1;14(1):61. PMID: 29490661; PMCID: PMC5831202. [CrossRef]
  67. Sebbag L, Allbaugh RA, Weaver A, Seo YJ, Mochel JP. Histamine-Induced Conjunctivitis and Breakdown of Blood-Tear Barrier in Dogs: A Model for Ocular Pharmacology and Therapeutics. Front Pharmacol. 2019 Jul 9;10:752. PMID: 31354477; PMCID: PMC6629934. [CrossRef]
  68. Sebbag L, Mochel JP. An eye on the dog as the scientist's best friend for translational research in ophthalmology: Focus on the ocular surface. Med Res Rev. 2020 Nov;40(6):2566-2604. Epub 2020 Jul 31. PMID: 32735080. [CrossRef]
  69. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, López CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG; Inflammation and Host Response to Injury, Large Scale Collaborative Research Program. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3507-12. Epub 2013 Feb 11. PMID: 23401516; PMCID: PMC3587220. [CrossRef]
  70. Sotillo S, Ward JL, Guillot E, Domenig O, Yuan L, Smith JS, Gabriel V, Iennarella-Servantez CA, Mochel JP. Dose-response of benazepril on biomarkers of the classical and alternative pathways of the renin-angiotensin-aldosterone system in dogs. Sci Rep. 2023 Feb 15;13(1):2684. PMID: 36792677; PMCID: PMC9932142. [CrossRef]
  71. Sun D, Yu LX, Hussain MA, Wall DA, Smith RL, Amidon GL. In vitro testing of drug absorption for drug 'developability' assessment: forming an interface between in vitro preclinical data and clinical outcome. Curr Opin Drug Discov Devel. 2004 Jan;7(1):75-85. PMID: 14982151.
  72. The COVE Study Group. Controlled clinical evaluation of enalapril in dogs with heart failure: results of the Cooperative Veterinary Enalapril Study Group. J Vet Intern Med. 1995 Jul-Aug;9(4):243-52. PMID: 8523321. [CrossRef]
  73. The IMPROVE Study Group. Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the Invasive Multicenter PROspective Veterinary Evaluation of Enalapril study. J Vet Intern Med. 1995 Jul-Aug;9(4):234-42. PMID: 8523320. [CrossRef]
  74. Tuttle KR, Wilson JM, Lin Y, Qian HR, Genovese F, Karsdal MA, Duffin KL, Botros FT. Indicators of Kidney Fibrosis in Patients with Type 2 Diabetes and Chronic Kidney Disease Treated with Dulaglutide. Am J Nephrol. 2023;54(1-2):74-82. Epub 2023 Feb 8. PMID: 36754023.
  75. Vaccari CS, Rahman ST, Khan QA, Cheema FA, Khan BV. Effects of angiotensin-converting enzyme inhibitor therapy on levels of inflammatory markers in response to exercise-induced stress: studies in the metabolic syndrome. J Cardiometab Syndr. 2008 Winter;3(1):12-7. PMID: 18326980. [CrossRef]
  76. Waanders F, de Vries LV, van Goor H, Hillebrands JL, Laverman GD, Bakker SJ, Navis G. Aldosterone, from (patho)physiology to treatment in cardiovascular and renal damage. Curr Vasc Pharmacol. 2011 Sep;9(5):594-605. PMID: 21529330. [CrossRef]
  77. Ward JL, Chou YY, Yuan L, Dorman KS, Mochel JP. Retrospective evaluation of a dose-dependent effect of angiotensin-converting enzyme inhibitors on long-term outcome in dogs with cardiac disease. J Vet Intern Med. 2021 Sep;35(5):2102-2111. Epub 2021 Aug 13. PMID: 34387901; PMCID: PMC8478030. [CrossRef]
  78. Ward JL, Guillot E, Domenig O, Ware WA, Yuan L, Mochel JP. Circulating renin-angiotensin-aldosterone system activity in cats with systemic hypertension or cardiomyopathy. J Vet Intern Med. 2022 May;36(3):897-909. Epub 2022 Mar 14. PMID: 35285549; PMCID: PMC9151484. [CrossRef]
  79. Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, Pairaudeau G, Pennie WD, Pickett SD, Wang J, Wallace O, Weir A. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov. 2015 Jul;14(7):475-86. Epub 2015 Jun 19. PMID: 26091267. [CrossRef]
  80. Wei R, Ma S, Wang C, Ke J, Yang J, Li W, Liu Y, Hou W, Feng X, Wang G, Hong T. Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner. Am J Physiol Endocrinol Metab. 2016 Jun 1;310(11):E947-57. Epub 2016 Apr 12. PMID: 27072494.
  81. Young M, Fullerton M, Dilley R, Funder J. Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest. 1994 Jun;93(6):2578-83. PMID: 8200995; PMCID: PMC294488. [CrossRef]
  82. Zdyrski C, Gabriel V, Ospina O, Wickham H, Sahoo DK, Dao K, Aguilar Meza LS, Ralston A, Bedos L, Bastian W, Honold S, Pineyro P, Douglass EF, Mochel JP, Allenspach K. A Multi-Tissue Comparison and Molecular Characterization of Canine Organoids. bioRxiv 2022.07.15.500059;. [CrossRef]
  83. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. Epub 2015 Sep 17. PMID: 26378978.
  84. Zushin PH, Mukherjee S, Wu JC. FDA Modernization Act 2.0: transitioning beyond animal models with human cells, organoids, and AI/ML-based approaches. J Clin Invest. 2023 Nov 1;133(21):e175824. PMID: 37909337; PMCID: PMC10617761. [CrossRef]
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