title: Hydrogen sulfide alleviates hypertensive kidney dysfunction through an epigenetic mechanism.
abstract: Hypertension is a major risk factor for chronic kidney disease (CKD), and renal inflammation is an integral part in this pathology. Hydrogen sulfide (H2S) has been shown to mitigate renal damage through reduction in blood pressure and ROS; however, the exact mechanisms are not clear. While several studies have underlined the role of epigenetics in renal inflammation and dysfunction, the mechanisms through which epigenetic regulators play a role in hypertension are not well defined. In this study, we sought to identify whether microRNAs are dysregulated in response to angiotensin II (ANG II)-induced hypertension in the kidney and whether a H2S donor, GYY4137, could reverse the microRNA alteration and kidney function. Wild-type (C57BL/6J) mice were treated without or with ANG II and GYY4137 for 4 wk. Blood pressure, renal blood flow, and resistive index (RI) were measured. MicroRNA microarrays were conducted and subsequent target prediction revealed genes associated with a proinflammatory response. ANG II treatment significantly increased blood pressure, decreased blood flow in the renal cortex, increased RI, and reduced renal function. These effects were ameliorated in mice treated with GYY4137. Microarray analysis revealed downregulation of miR-129 in ANG II-treated mice and upregulation after GYY4137 treatment. Quantitation of proteins involved in the inflammatory response and DNA methylation revealed upregulation of IL-17A and DNA methyltransferase 3a, whereas H2S production enzymes and anti-inflammatory IL-10 were reduced. Taken together, our data suggest that downregulation of miR-129 plays a significant role in ANG II-induced renal inflammation and functional outcomes and that GYY4137 improves renal function by reversing miR-129 expression.NEW & NOTEWORTHYWe investigated epigenetic changes that occur in the hypertensive kidney and how H2S supplementation reverses adverse effects. Inflammation, aberrant methylation, and dysfunction were observed in the hypertensive kidney, and these effects were alleviated with H2S supplementation. We identify miR-129 as a potential regulator of blood pressure and H2S regulation.
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Weber
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Sathnur B
authors.initials: SB
authors.lastname: Pushpakumar
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky u0sen001@louisville.edu.
authors.forename: Utpal
authors.initials: U
authors.lastname: Sen
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D006862:Hydrogen Sulfide / Q000627:therapeutic use*; D006973:Hypertension / Q000150:complications*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics; D007672:Kidney Cortex / Q000098:blood supply; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D046228:Microarray Analysis; D009025:Morpholines / Q000627:therapeutic use; D009946:Organothiophosphorus Compounds / Q000627:therapeutic use; D012079:Renal Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; C000715535:Dnmt3a protein, mouse; C529376:GYY 4137; D035683:MicroRNAs; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D000804:Angiotensin II; D000090205:DNA Methyltransferase 3A; D006862:Hydrogen Sulfide
keywords: hydrogen sulfide; hypertension; inflammation; microRNA