Spatiotemporal regulation of hydrogen sulfide signaling in the kidney

Abstract

Hydrogen sulfide (H₂S) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, H₂S is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. H₂S-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, H₂S is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of H₂S are not precisely understood. H₂S modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, H₂S affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by H₂S. H₂S enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of H₂S anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal H₂S levels. Together, H₂S is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of H₂S not only expands fundamental insight in the regulation of functional effects mediated by H₂S, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.

Keywords: Gasotransmitter; Hydrogen sulfide; Hypoxia; Ischemia-reperfusion injury; Kidney; Persulfidation.