Post severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, Covid-19) sequalae’s, immune and RNA based treatments are associated with the development of micro-stones and chronic kidney disease (CKD). In addition, circulating cytokines cocktail and viral envelope spike protein (SP) instigates CKD. During epigenetic regulation, Covid-19 methyltransferase (MT) methylates the DNA/RNA/Proteins/Histones and generates homocysteine (Hcy). Although cysteine promotes the growth and aggregation of calcium oxalate crystals in normal undiluted human urine. However, during elevated levels of Hcy (i.e., hyperhomocysteinemia, HHcy) due in part to the impaired transsulfuration (i.e., mitochondrial sulfur metabolism) pathways, homocysteine is the only sulfur-denoting non-protein amino acid may promote crystals. HHcy is associated with severity of Covid-19 infection and pneumonia post Covid-19. It is unclear however whether the HHcy facilitates homocysteine crystals. Although an E. coli strain degrades tricarboxylic acid (TCA, citric acid), and disrupts mitochondrial TCA cycle, to dicarboxylic acid (DCA, oxalic acid), DCA also promotes calcium oxalate crystals and may contributes to kidney stones, it is unclear whether gut-dysbiosis by Covid-19 infection contributes to kidney stones. There is robust succinylation of enzymes in TCA cycle which causes dysfunctional mitochondrial bioenergetics during Covid-19 infection. In this regards interaction between SIRT5 and mitochondrial transsulfuration during Covid-19 infection attenuates TCA cycle. Interestingly, the mitochondrial bioenergetics though sulfur metabolism participate in TCA cycle and epigenetic acetylation/succinylation, therefore, Covid-19 infection transition acute kidney injury (AKI) to CKD by defective mitochondria sulfur metabolism (transsulfuration) pathways, forming uricemia micro stones.

The chronic high fat dysbiosis diet (HFD) instigates cardiac remodeling, dysfunction and chronic heart failure (CHF). The therapeutic approaches focusing oxidative stress, inflammation and hyperlipidemia have not yielded significant positive clinical outcomes. Recent studies report that although mitochondrial ATP citrate lyase (ACLY) supports cardiac function, however, decreases more in human HFpEF than HFrEF. Interestingly, the ACLY synthesizes lipids and creates hyperlipidemia. Epigenetically, ACLY acetylates histone. The mechanism(s) are unknown. One hypothesis is that the HFD induces epigenetic folate 1-carbon metabolism (FOCM), heperhomocysteinemia (HHcy, a cause of abrogation of sleep-time dipping in blood pressure and hypertension) and heart failure. Interestingly, the probiotics utilizes the fat/lipids post-biotically, and increases the mitochondrial bioenergetics and attenuates the HFD induced heart failure. We suggest a novel and paradigm-shift epigenetic mitochondrial sulfur transsulfuration pathways that selectively target HFD-induced CHF. The HFD via transport and metabolomic pathways instigates cardiac remodeling and dyfunction. Previous studies from our laboratory, using a single cell analysis, revealed increase in transporter (SLC25A) of s-adenosine-methionine (SAM) during elevated levels of homocysteine (Hcy, i.e., hyperhomocysteinemia, HHcy), a consequence of impaired epigenetic recycling of Hcy back to methionine by increase in FOCM methylation of H3K4, K9, H4K20 and gene writer (DNMT) and decrease in eraser (TET/FTO). The Hcy transported to mitochondria by SLC7A for clearance via sulfur metabolomic transsulfuration by 3-mercaptopyruvate sulfur transferase (3MST). Interestingly, the HHcy decreases ATP, OCR, H₂S, PGC1α, TFAM, and increase in fission/fusion ratio, causing mitochondria dysfunction. We suggest that gut dysbiosis by HFD disrupts rhythmic epigenetic memory via FOCM and increase in DNMT1 and creates HHcy, leading to decrease mitochondrial transsulfuration and bioenergetics. The treatment with a probiotic, lactobacillus will eat the fat/lipids post-biotically and bi-directionally will produce folic acid and lactone-ketone body that will mitigate the HFD-induced mitochondrial remodeling and heart failure.

Although renal denervation (RDN) protects against hypertension, hypertrophy, and heart failure (HF), it is not clear whether RDN preserves ejection fraction (EF) during heart failure (HFpEF). To test this hypothesis, we simulated chronic congestive cardiopulmonary heart failure (CHF) by creating aorta-vena cava fistula (AVF) in C57BL/6J wild type (WT) mice. There are four ways to create experimental CHF: (1) myocardial infarction (MI) which is basically ligating coronary by instrumenting and injuring the heart; (2) trans-aortic constriction (TAC), although it mimics systematic hypertension but TAC again constricts aorta on top of the heart and exposes the heart; (3) acquired CHF such as by dietary factors, diabetes/salt diets etc. but it is multifactorial, and finally (4) AVF, which is the only one wherein AVF is created ~1cm below the kidney where the aorta and vena cava share the common middle-wall. By creating fistula, the red blood enters vena cava without an injury to the heart. This model mimics CHF such as during aging where with age the preload keeps increasing than the aging heart can pump out due to the weakened cardiac myocytes. This also involves the right ventricle to lung to left ventricle flow, thus creating congestion. The heart in AVF goes to transition from preserved to reduced EF (i.e., HFpEF to HFrEF). In fact, there are more models of volume overload, such as the pacing-induced and mitral valve regurgitation but these are also injurious models. Our lab is one of the original labs in creating and studying the AVF phenotype. The RDN was created by treating the cleaned bilateral renal artery. After 6 weeks, blood, heart, and renal samples were analyzed for exosome, cardiac regeneration markers and renal cortex proteinases. Cardiac function was analyzed by echocardiogram (ECHO). Fibrosis was analyzed with trichrome staining. The results suggested that there was robust increase in exosomes’ level in AVF blood, suggesting compensatory systemic response during AVF-CHF. During AVF there was no change in cardiac eNOS, Wnt1 and β-catenin, however; during RDN there was robust increase in eNOS, Wnt1 and β-catenin compared to the sham group. As expected in HFpEF there was perivascular fibrosis, hypertrophy and pEF. Interestingly, increased levels of eNOS suggested that despite fibrosis, the NO generation was higher that most likely contributed to pEF during HF. The RDN intervention revealed an increase in renal cortical caspase 8 and a decrease in caspase 9. Since caspase 8 is protective and caspase 9 is apoptotic, we suggest that RDN protects against renal stresses, and apoptosis. Our findings also suggest that RDN is cardioprotective during HFpEF via the preservation of eNOS and accompanied endocardial-endothelial function.