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.

Fig. 1

Metabolism of H₂S. In the canonical pathway of H₂S production, l-homocysteine is converted to cystathionine by CBS, which is then converted to l-cysteine by CSE. H₂S is produced from l-cysteine by both CBS and CSE. A second pathway is the production of H₂S by conversion of d-cysteine or α-ketoglutarate to 3-mercaptopyruvate by DAO and CAT respectively, which is subsequently converted to H₂S by 3-MST. H₂S catabolism occurs through persulfidation of proteins, via the formation of sulfane sulfur species, such as thiosulfate via SQR. Catabolism also occurs through the production of methyl mercaptan, also known as methanethiol, to form dimethyl sulfide. A non-enzymatic pathway allows H₂S to bind to methemoglobin to form sulfhemoglobin.

Fig. 2

PTP1B persulfidation attenuates ER stress. In endoplasmic reticulum stress, a condition caused by accumulation of mis- or unfolded proteins, protein kinase R-like endoplasmic reticulum kinase (PERK) is phosphorylated. This renders protein tyrosine phosphatase 1B (PTP1B) active, which contributes to ER stress. PERK phosphorylation also leads to translocation of the transcription factor Activating transcription factor 4 (ATF4), which enhances expression of CSE. CSE then produces H₂S, which persulfidate active PTP1B at Cys215, rendering it inactive and attenuating ER stress.

Fig. 3

Renal H₂S signaling can be cytoprotective. Spatiotemporal H₂S anabolism is regulated by local pH, enzyme optima (table inset), enzyme localization and substrate availability. H₂S metabolites such as sulfane sulfur or acid-labile pools can reversibly contribute to H₂S production and signaling. H₂S signaling regulates renal blood pressure via interaction with NO signaling, and systemic blood pressure by regulating gene expression of components of the renin-angiotensin system. ROS species are directly and indirectly (via glutathione and others) scavenged by H₂S. At low concentrations H₂S is an alternative electron donor for oxidative phosphorylation, maintaining ATP production in hypoxic conditions. Further, cysteine persulfidation by H₂S modulates protein activity, localization, protein-protein interactions, transcription factor activity and protects cysteine moieties from detrimental post-translational modifications. During proteotoxic stress, H₂S activates the UPR, modulates autophagic flux and proteasome activity. Thereby renal H₂S signaling is cytoprotective, and contributes to renal functioning. AL-H₂S: acid-labile H₂S, OxPhos: oxidative phosphorylation, RAS axis: renin-angiotensin system axis, TF activity: transcription factor activity, TRX: thioredoxin, UPR: unfolded protein response. Synthesizing enzymes are shown if known, bolder characters indicate more experimental evidence. When no enzyme is mentioned, studies were performed with H₂S donors or the producing enzyme is simply not known. Figure created with BioRender.com.