The roles of hydrogen sulfide in renal physiology and disease states

Figures & data

Figure 1. Endogenous synthesis of H₂S by four pathways. (A) CSE catalyzes the reaction of L–homocysteine to induce the production of H₂S. (B) CBS reacts with L–homocysteine, increasing the generation of L–cystathionine, which is then converted into L–cysteine via CSE, which further produces H₂S. (C) L–cysteine is converted into 3MP by CAT, and 3–MST catalyzes the reaction of 3MP to induce H₂S generation in mitochondria. (D) DAO reacts with D–cysteine to generate 3MP, which then enters mitochondria and serves as a substrate for the production of H₂S. CBS (cystathionine β–synthase); CSE (cystathionine γ–lyase); CAT (cysteine aminotransferase); 3MP (3–mercaptopyruvate); DAO (D–amino acid oxidase); 3–MST (3–mercaptopyruvate sulfurtransferase).

Table 1. Previous studies on the effects of H₂S in acute kidney injury.

Model	Protocol	Treatment	Dose	Effect of H2S	Mechanism	Reference
male C57BL/6 mice ischemia/reperfusion injury	I (30 min)/R (8 days)	NaHS	500 μg kg^–1 BW	–accelerated the recovery of renal function and tubule morphology	–reduced post–I/R superoxide formation, lipid peroxidation, GSSG/GSH level and Nox4 expression –increased catalase and SOD expression	[37]
CSE^−/− mice ischemia/reperfusion injury	I (30 min)/R (1 day)	intraperitoneal injection of NaHS 15 min before surgery	1 mg kg^–1	–decreased mortality and severity of damage	–regulated the amount of ROS associated with hypoxic stress	[38]
male Wistar rats ischemia/reperfusion injury	I (50 min)/R (1 day)	intraperitoneal injections of NaHS 10 min before the onset of ischemia and immediately after the onset of reperfusion	75 μmol kg^–1	–attenuated the severity of the structural changes	–reduced oxidative stress	[39]
male C57BL/6 mice Cisp–induced AKI	Single injection of 16 mg kg^–1 Cisp	intraperitoneal injections of NaHS for 4 days	5.6 mg kg^–1 day^–1	–prevented mitochondrial dysfunction –increased ATP generation –decreased oxidative injury	–increased S–sulfhydration of SIRT3 –induced deacetylation of OPA1, ATP synthase β, and superoxide dismutase 2 protein	[53]
male Sprague–Dawley rats Cisp–induced AKI	injection of 6 mg kg^–1 Cisp	single dose of NaHS	100 µmol kg^–1	–attenuated proximal tubular cell apoptosis and mesangial matrix	–exhibited antioxidant properties	[56]
male Sprague–Dawley rats Cisp–induced AKI	injection of 25 mg kg^–1 Cisp	intraperitoneal injections of NaHS and CYY4137 for 4 days	NaHS 5.6 mg kg^–1 GYY4137 100 mg kg^–1	–attenuated proximal tubule cell death and nephrotoxicity	–suppressed intracellular ROS generation –blocked downstream MAPKs by inhibiting NADPH oxidase activity	[65]
male C57BL/6 mice Cisp–induced AKI	injection of 25 mg kg^–1 Cisp	intraperitoneal injections of NaHS and CYY4137 for 4 days	NaHS 5.6 mg kg^–1 GYY4137 100 mg kg^–1	–reduced tubular injury	–suppressed the massive production of inflammatory cytokines –decreased phosphorylation of STAT3 and IKKβ –mitigated phosphorylation and degradation of IκBα	[66]
male Swiss albino mice LPS–induced AKI	injection of 10 mg kg^–1 LPS 6 h	intraperitoneal injections of NaHS 30 min before LPS	14 μmol kg^–1	–damaged glomerular hypercellularity	–exhibited proinflammatory activity	[64]
male wild–type C57BL/6 J mice LPS–induced AKI	injection of 5 mg kg^–1 LPS 6 h	intraperitoneal injections of NaHS 3 h after LPS	50 μmol kg^−1	–improved renal function and attenuated kidney histopathological changes	–inhibited inflammation and oxidative stress via the TLR4/NLRP3 signaling pathway	[67]
male C57BL/6 mice LPS–induced AKI	injection of 10 mg kg^–1 LPS 12 h	intraperitoneal injections of NaHS 30 min before LPS	0.8 mg kg^–1	–improved edema and granular degeneration of tubular epithelial cells	–promoted autophagy –inhibited apoptosis –induced release of inflammatory factors	[68]

Abbreviations: NaHS (sodium hydrosulfide); I/R (ischemic/reperfusion); GSSG (glutathione disulfide); GSH (glutathione); SOD (superoxide dismutase); CSE (cystathionine gamma–lyase); ROS (reactive oxygen species); STAT3 (signal transducer and activator of transcription 3); OPA1 (optic atrophy 1); IKKβ (IkappaB kinase beta); IκBα (IkappaB alpha); LPS (lipopolysaccharide); TLR4 (toll–like receptor 4); NLRP3 (NOD–like receptor family pyrin domain–containing 3).

Table 2. Previous studies on the effects of H₂S in diabetic nephropathy.

Model	Protocol	Treatment	Dose	Effect of H2S	Mechanism	Reference
male C57BL/6 mice	injection of STZ 100 mg kg^–1 8 weeks	injection with Na2S4 for the next 4 weeks.	500 μg kg^–1 day^–1	–attenuated renal fibrosis and renal cell apoptosis –ameliorated renal dysfunctional and histological damage	–inhibited overproduction of inflammation cytokines and ROS –inactivated p65 NF–κB and STAT3 phosphorylation/acetylation through sulfhydration of SIRT1	[92]
male C57BL/6J mice	injection of STZ 50 mg kg^–1 4 days	injection with CYY4137 for 12 weeks	20 mg kg^–1 day^–1	–ameliorated mesangial matrix expansion and glomerular basement membrane thickening –ameliorated albuminuria	–reversed the increases in ubiquitinated CBS and nitrotyrosine in the kidneys	[93]
male Wistar–Kyoto rats	injection of STZ 60 mg kg^–1 for 3 weeks	intraperitoneal injections of NaHS for 4 weeks	56 μmol kg^–1	–attenuated the severity of the structural changes	–reduced oxidative stress –augmented the antioxidant effect	[94]
diabetic C57BL/6–Ins2Akita/J mice	/	intraperitoneal injections of GYY for 8 weeks	0.25 mg kg^−1 day^−1	–improved renal fibrosis	–modulated PPAR/RAR–mediated RXR signaling to ameliorate PAI–1–dependent adverse extracellular matrix turnover	[95]
male Sprague–Dawley rats	injection of STZ 50 mg kg^–1	intraperitoneal injections of NaHS after injection of STZ	56 mmol kg^−1 day^−1	–improved kidney function	–activated KАTP channels to affect antioxidants and NO –decreased proinflammatory cytokines	[96]
male Sprague–Dawley rats	injection of STZ 65 mg kg^–1	intraperitoneal injections of SPRC for 9 weeks	10, 25, 50 mg kg^–1 day^–1	–improved renal function –inhibited renal fibrosis	–inhibited inflammatory reaction mediated by IL–1β, TNF–α, MCP–1 and Stat3 –suppressed the expression of TGF–β1 expression and inhibited the phosphorylation of ERK and p38	[97]
male white albino rats	injection of STZ 60 mg kg^–1	intraperitoneal injections of NaHS for 30 days	NaHS 30 µmol kg^–1 day^–1 NaHS 100 µmol kg^–1 day^–1	–improved renal function	–decreased FBS, ROS and apoptosis –upregulated SIRT1	[98]
male Sprague–Dawley rats	injection of STZ 40 mg kg^–1	intraperitoneal injections of NaHS	100 µmol kg^–1 day^–1	–improved renal fibrosis	–downregulated TGF–1	[99]

Abbreviations: ROS (reactive oxygen species); NF–κB (nuclear factor κB); NF–κB (nuclear factor κB); STAT3 (signal transducer and activator of transcription 3); SIRT1 (sirtuin1); CBS (cystathionine beta–synthase); PPAR (peroxisome proliferator–activated receptors); RAR (retinoic acid receptor); RXR (retinoid X receptor); PAT–1 (putative anion transporter 1); IL–1β (interleukin–1beta); TNF–α (tumor necrosis factor alpha); MCP–1 (Monocyte chemoattractant protein–1); TGF–β1(transforming growth factor beta1); ERK (extracellular signal–regulated kinase); FBS (fasting blood glucose).

Figure 2. Mechanisms underlying the protective effect of H₂S in DN. (A) H₂S stimulates NO formation, which reduces NOX4 levels; H₂S activates AMPK, thereby suppressing mTOR signaling; and H₂S activates the Nrf2 pathway. (B) H₂S acts as an anti–inflammatory factor by blocking NF–κB signaling in the renal system. (C) Renin converts AGT into Ang I. Under the action of ACE, Ang I is further converted to Ang II, and Ang II binds to AT–1, which exacerbates DN. The activation of RAAS in DN is ameliorated by H₂S treatment via inhibition of AGT, renin, ACE, Ang II and AT–1 receptors. OS (Oxidative stress); AMPK (AMP–activated protein kinase); NO (nitric oxide); mTOR (mechanistic target of rapamycin); Nrf (Nuclear factor–erythroid 2–related factor 2); NOX4 (NADPH oxidase 4). TNF–α (tumor necrosis factor α); IL–1β (interleukin–1β); VCAM–1 (vascular cell adhesion molecule–1); ICAM–1(intercellular adhesion molecule–1); MCP–1 (monocyte chemotactic protein–1); MMP–9 (matrix metalloproteinase–9). AGT (Angiotensinogen); ACE (angiotensin converting enzyme); AngI (angiotensin I); AngII (angiotensin II); AT–1 (Ang II type I receptor1).

Table 3. Previous studies on the effects of H₂S in obstructive kidney disease.

Model	Treatment	Dose	Effects of H2S	Mechanism	Reference
male C57BL/6 male mice	NaHS	1.12, 5.6, or 28 μg kg^–1 BW	–exerted antifibrotic effects	–preservation of antioxidant enzymes –inhibits activation of TGF–β/Smad 3 signals – mitigates activation of NF–κB and inflammation.	[145]
male Sprague–Dawley rats	NaHS intraperitoneally once daily 3 days before surgery and continued for 1 to 2 weeks after operation	5.6, 56, and 560 μg kg^–1 day^–1	–inhibited the proliferation and differentiation of renal fibroblasts	–downregulate the expressions of proliferation–related genes –block the TGF–β1–Smad signaling –blockade of MAPK kinases activation	[146]
male Lewis rats	GYY4137 intraperitoneally continued for 30 days after operation	200 μmol kg^–1 day^–1	–decreased Scr and the ACR –mitigated cortical loss –mitigated tubulointerstitial fibrosis	–exerted anti–inflammatory effects –alleviated EMT progression	[147]
male Lewis rats	GYY4137 intraperitoneally continued for 14 and 30 days after operation	200 μmol kg^–1 day^–1	–accelerated the recovery of renal function –attenuated renal injury	–regulated the TGF–β1–mediated EMT pathway	[148]
C57/BL6 mice	NaHS	50 μg kg^–1 day^–1	–attenuated renal damage and fibrosis	–inhibited M1 and M2 macrophage infiltration –suppressed NLRP3 activation, inactivated NF–κB and IL4/STAT6 signaling	[144]
male Wistar rats	NaHS intraperitoneally 3 days before surgery and continued for 9 days after operation	5 mg kg^–1 day^–1	–reduced tubulointerstitial injury	–exerted antioxidant effects (reduced MDA levels, increased SOD levels) –exerted anti–inflammatory effects (reduced TNF–α levels)	[149]
male Wistar albino rats	NaHS intraperitoneally 14 days after operation	56 μmol kg^–1 day^–1	–reduced tubular necrosis	–exerted antioxidant effects (improved oxidant status) –exerted anti–inflammatory effects	[150]
male C57BL/6 mice	NaHS intraperitoneally once daily 3 days before surgery and continued for 1 to 2 weeks after operation	–	–protected vascular endothelial cells	–reduced excessive autophagy (suppressed the ROS–AMPK pathway)	[151]

Abbreviations: NaHS (sodium hydrosulfide); Scr (serum creatinine); ACR (urine protein–to–creatinine excretion ratio); EMT (epithelial–mesenchymal transition); MDA (malondialdehyde); SOD (superoxide dismutase); NF–κB (nuclear factor κB); MAPK (mitogen–activated protein kinase).

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