Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension

Abstract

Over the past several years, hydrogen sulfide (H₂S) has been shown to be an important player in a variety of physiological functions, including neuromodulation, vasodilation, oxidant regulation, inflammation, and angiogenesis. H₂S is synthesized primarily through metabolic processes from the amino acid cysteine and homocysteine in various organ systems including neuronal, cardiovascular, gastrointestinal, and kidney. Derangement of cysteine and homocysteine metabolism and clearance, particularly in the renal vasculature, leads to H₂S biosynthesis deregulation causing or contributing to existing high blood pressure. While a variety of environmental influences, such as diet can have an effect on H₂S regulation and function, genetic factors, and more recently epigenetics, also have a vital role in H₂S regulation and function, and therefore disease initiation and progression. In addition, new research into the role of gut microbiota in the development of hypertension has highlighted the need to further explore these microorganisms and how they influence the levels of H₂S throughout the body and possibly exploiting microbiota for use of hypertension treatment. In this review, we summarize recent advances in the field of hypertension research emphasizing renal contribution and how H₂S physiology can be exploited as a possible therapeutic strategy to ameliorate kidney dysfunction as well as to control blood pressure.

Keywords: Epigenetics; Extracellular matrix; Folic acid; Homocysteine; Inflammation; MMPs; Microbiota; Polysulfides; TIMPs; miRNA.

Figure 1

Schematic of CKD mechanism in hypertension depicting important roles of Hyperhomocysteinemia and H₂S. Hypertension causes renal impairment of H₂S producing enzymes leading to H₂S deficiency and increase mitochondrial generated oxidative inflammation (on the left side). Through a different but related mechanism of H₂S deficiency (since homocysteine is a precursor of H₂S, homocysteine accumulation, i.e, Hyperhomocysteinemia diminishes H₂S production), hypertension increases resistive index and reduces blood flow in the renal vasculature (on the right). As a result kidney impairment occurs and homocysteine clearance impairs. High levels of homocysteine in turn activate miRNAs leading to pro-fibrotic gene activation and fibrosis. These above described two vicious cycles worsen CKD in hypertension.

Figure 2

Schematic of hypertension-induced epigenetic mechanism of kidney dysfunction. Ang-II causes disruption of epigenetic mechanisms (methylation, histone modification, non-coding RNAs) leading to inflammation and increased vascular resistance causing kidney dysfunction in hypertension. GYY4137 alleviates these effects and improves kidney function. DNA methyltransferase DNMT3a and pro-inflammatory cytokine IL-17 are increased in the hypertensive kidney while miR-129 is suppressed [68]. The miR-129 is predicted to target and regulate both DNMT3a and IL-17 and its expression is increased with H₂S donor GYY4137 treatment, leading to a decrease in IL-17 and DNMT3a expression [68].

Figure 3

Schematic of Homocysteine metabolism and H₂S biosynthesis. H₂S; hydrogen sulfide; TH4-folate, tetrahydrofolate; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; 3MST, 3-mercaptopyruvate sulfurtransferase; AAT, aspartate aminotransferase.

Figure 4

Schematic of H₂S biosynthesis form cysteine. Metabolism of l-cysteine by cysteine aminotransferase (CAT) and d-cysteine by d-amino acid oxidase (DAO) produces 3-mercaptopyruvate (3MP). 3MP then metabolizes to produce H₂S by 3-mercaptopyruvate sulfurtransferase (3MST).