Spatiotemporal regulation of hydrogen sulfide signaling in the kidney

Hydrogen sulfide (H(2)S) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, H(2)S is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. H(2)S-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, H(2)S is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of H(2)S are not precisely understood. H(2)S modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, H(2)S 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 H(2)S. H(2)S 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 H(2)S anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal H(2)S levels. Together, H(2)S is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of H(2)S not only expands fundamental insight in the regulation of functional effects mediated by H(2)S, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.