For decades, hydrogen sulfide (H2S) was known only for its neurotoxicity and as an environmental hazard. Recent findings however, suggest that endogenous H2S has a variety of physiological functions and a decrease in production can lead to vascular dysfunction, atherosclerosis and hypertension. This discovery has stimulated further research into its development as a potential therapeutic agent in diseases attributed to diminished H2S synthesis. In chronic kidney disease, low levels of plasma H2S is often associated with a concomitant increase in homocysteine (Hcy), known as hyperhomocysteinemia (HHcy). HHcy is well known to cause vascular dysfunction. The cause and effect relationship of HHcy in renal disease can therefore adversely affect the final outcome. Because Hcy is a precursor of H2S, changes in the H2S metabolism can have a significant impact on HHcy-induced pathology. However, the mechanism by which HHcy causes vascular dysfunction and the role of H2S in renal protection is incompletely understood. In the body, Hcy is metabolized by three enzymes, cystathionine ?-synthase (CBS), cystathionine y-lyase (CSE) and 3- mercaptopyruvate sulfurtransferase (3MST) and produce H2S. During HHcy, an impairment in these enzymes leads to deficient H2S production. Our preliminary studies suggest that HHcy results in upregulation of caveolin-1 and homocysteinylation of eNOS thus decreasing NO production. The resulting imbalance in matrix metalloproteinases and their tissue inhibitors of metalloproteinases causes accumulation of extracellular matrix proteins leading to microvascular remodeling, renal dysfunction and hypertension. In this proposal, we hypothesize that H2S offers renal protection from HHcy-induced renal damage by inhibition of caveolin-1 and modulation of eNOS. We will test this hypothesis in vivo and in vitro. Wild type (C57BL/6J) and genetic model of HHcy (CBS+/-) mice will be supplemented without or with H2S. To determine whether HHcy effects are caveolin-1 dependent we will use caveolin-1-/- mice supplemented with high Hcy diet. To ameliorate the HHcy- induced injury, single, double or triple gene delivery system employing CBS, CSE and 3MST enzymes will be used to enhance conversion of Hcy to H2S. In addition to confirming the preliminary findings, further studies will be performed for a deeper understanding into H2S-mediated improvement in renovascular dysfunction caused by pro-fibrotic and pro-inflammatory effects of HHcy. This research is novel because it evaluates gene delivery as a therapeutic option to ameliorate HHcy-induced microvascular remodeling, renal dysfunction and hypertension.
A non-protein amino acid homocysteine at elevated levels cause vascular remodeling and dysfunction. Homocysteine however in the body metabolizes and produces hydrogen sulfide. Although high levels of hydrogen sulfide are toxic, low levels are protective against varieties of vascular diseases. This study proposes to mitigate high homocysteine effects on renal vascular tissues either by hydrogen sulfide supplementation or through conversion of bad homocysteine to good hydrogen sulfide by gene manipulation. The research outcome will further our knowledge for future investigations of therapeutic potential of hydrogen sulfide in high homocysteine-associated renovascular diseases.
|Weber, Gregory J; Foster, Jaleyea; Pushpakumar, Sathnur B et al. (2018) Altered microRNA regulation of short chain fatty acid receptors in the hypertensive kidney is normalized with hydrogen sulfide supplementation. Pharmacol Res 134:157-165|
|Theilen, Nicholas T; Kunkel, George H; Tyagi, Suresh C (2017) The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy. J Cell Physiol 232:2348-2358|
|Veeranki, Sudhakar; Tyagi, Suresh C (2017) Dysbiosis and Disease: Many Unknown Ends, Is It Time to Formulate Guidelines for Dysbiosis Research? J Cell Physiol 232:2929-2930|
|Pushpakumar, Sathnur; Ren, Lu; Kundu, Sourav et al. (2017) Toll-like Receptor 4 Deficiency Reduces Oxidative Stress and Macrophage Mediated Inflammation in Hypertensive Kidney. Sci Rep 7:6349|
|John, A M Sashi Papu; Kundu, Sourav; Pushpakumar, Sathnur et al. (2017) GYY4137, a Hydrogen Sulfide Donor Modulates miR194-Dependent Collagen Realignment in Diabetic Kidney. Sci Rep 7:10924|
|Muradashvili, Nino; Tyagi, Suresh C; Lominadze, David (2017) Localization of Fibrinogen in the Vasculo-Astrocyte Interface after Cortical Contusion Injury in Mice. Brain Sci 7:|
|Veeranki, Sudhakar; Gandhapudi, Siva K; Tyagi, Suresh C (2017) Interactions of hyperhomocysteinemia and T cell immunity in causation of hypertension. Can J Physiol Pharmacol 95:239-246|
|Weber, Gregory J; Pushpakumar, Sathnur B; Sen, Utpal (2017) Hydrogen sulfide alleviates hypertensive kidney dysfunction through an epigenetic mechanism. Am J Physiol Heart Circ Physiol 312:H874-H885|
|Muradashvili, Nino; Tyagi, Reeta; Tyagi, Neetu et al. (2016) Cerebrovascular disorders caused by hyperfibrinogenaemia. J Physiol 594:5941-5957|
|Chernyavskiy, Ilya; Veeranki, Sudhakar; Sen, Utpal et al. (2016) Atherogenesis: hyperhomocysteinemia interactions with LDL, macrophage function, paraoxonase 1, and exercise. Ann N Y Acad Sci 1363:138-54|
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