In order to investigate the protective mechanism of hydrogen sulfide (H₂S) in sepsis‐associated acute kidney injury (SA‐AKI), ten AKI patients and ten healthy controls were enrolled. In AKI patients, levels of creatinine (Cre), urea nitrogen (BUN), tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β), and myeloperoxidase (MPO) activity as well as concentrations of malondialdehyde (MDA) and hydrogen peroxide (H₂O₂) were significantly increased compared with those of controls. However, plasma level of H₂S decreased and was linearly correlated with levels of Cre and BUN. After that, an AKI mouse model by intraperitoneal lipopolysaccharide (LPS) injection was constructed for in vivo study. In AKI mice, H₂S levels decreased with the decline of 3‐MST activity and expression; similar changes were observed in other indicators mentioned above. However, the protein expressions of TLR4, NLRP3, and caspase‐1 in mice kidney tissues were significantly increased 6 h after LPS injection. NaHS could improve renal function and kidney histopathological changes, attenuate LPS‐induced inflammation and oxidative stress, and inhibit expressions of TLR4, NLRP3, and caspase‐1. Our study demonstrated that endogenous H₂S is involved in the pathogenesis of SA‐AKI, and exogenous H₂S exerts protective effects against LPS‐induced AKI by inhibiting inflammation and oxidative stress via the TLR4/NLRP3 signaling pathway.

Reductions in hydrogen sulfide (H₂S) production have been implicated in the pathogenesis of hypertension; however, no studies have examined the functional role of hydrogen sulfide in hypertensive heart disease. We hypothesized that the endogenous production of hydrogen sulfide would be reduced and exogenous hydrogen sulfide would ameliorate cardiac dysfunction in N^ω-nitro- L-arginine methyl ester ( L-NAME)-induced hypertensive rats. Therefore, this study investigated the cardioprotective effects of hydrogen sulfide on L-NAME-induced hypertensive heart disease and explored potential mechanisms. The rats were randomly divided into five groups: Control, Control + sodium hydrosulfide (NaHS), L-NAME, L-NAME + NaHS, and L-NAME + NaHS + glibenclamide (Gli) groups. Systolic blood pressure was monitored each week. In Langendorff-isolated rat heart, cardiac function represented by ±LV dP/dt_max and left ventricular developing pressure was recorded after five weeks of treatment. Hematoxylin and Eosin and Masson’s trichrome staining and myocardium ultrastructure under transmission electron microscopy were used to evaluate cardiac remodeling. The plasma nitric oxide and hydrogen sulfide concentrations, as well as nitric oxide synthases and cystathionine-γ-lyase activity in left ventricle tissue were determined. The protein expression of p-Akt, Akt, p-eNOS, and eNOS in left ventricle tissue was analyzed using Western blot. After five weeks of L-NAME treatment, there was a time-dependent hypertension, cardiac remodeling, and dysfunction accompanied by a decrease in eNOS phosphorylation, nitric oxide synthase activity, and nitric oxide concentration. Meanwhile, cystathionine-γ-lyase activity and hydrogen sulfide concentration were also decreased. NaHS treatment significantly increased plasma hydrogen sulfide concentration and subsequently promoted the Akt/eNOS/NO pathway which inhibited the development of hypertension and attenuated cardiac remodeling and dysfunction. The cardioprotective effects of NaHS were counteracted by Gli which inhibited the Akt/eNOS/NO pathway. This suggests that the effects of hydrogen sulfide were mediated by the activation of the K_ATP channels. In conclusion, hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease via the activation of the Akt/eNOS/NO pathway, which was mediated by K_ATP channels. Impact statement: 1. We found that H₂S ameliorated L-NAME-induced cardiac remodeling and dysfunction, and played a protective role in L-NAME-induced hypertensive heart disease, which the existing studies have not reported. 2. H₂S activated the Akt/eNOS/NO pathway, thereby playing a cardioprotective role in L-NAME-induced hypertensive heart disease. 3. The cardioprotective effect of H₂S was mediated by ATP-sensitive potassium channels.

Objective: We aimed to elucidate the ameliorative effect of hydrogen sulfide (H₂S) on endothelium-dependent relaxation disturbances via peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase (PPARδ/eNOS) pathway activation in hypertensive patients and rats. Methods: Renal arteries were collected from normotensive and hypertensive patients who underwent nephron-sparing surgery. Renal arteries from 37 patients were cultured with or without sodium H₂S (NaHS) 50 μmol/l. The rats were randomly divided into four groups: Sham; Sham + NaHS, two kidneys; one clipped (2K1C); and 2K1C + NaHS. Mean arterial pressure was measured by tail-cuff plethysmography. A microvessel recording technique was used to observe the effect of NaHS on endothelium-dependent relaxation. Plasma H₂S concentrations were detected using the monobromobimane method. Real-time PCR and western blotting were used to assess mRNA and protein levels of AT1, cystathionine γ-lyase, PPARδ, and phosphor-eNOS. Laser confocal scanning microscopy measured intracellular NO production in human umbilical vein endothelial cells. Results: NaHS improved endothelial function in hypertensive humans and rats. The 20-week administration of NaHS to 2K1C rats lowered the mean arterial pressure. In human umbilical vein endothelial cells, NaHS improved the AngII-induced production of NO. NaHS upregulated PPARδ expression, increased protein kinase B (Akt) or adenosine monophosphate kinase-activated protein kinase (AMPK) phosphorylation, and enhanced eNOS phosphorylation. A PPARδ agonist could mimic the ameliorative effect of NaHS that was suppressed by PPARδ, AMPK, or Akt inhibition. Conclusion: H₂S plays a protective function in renal arterial endothelium in hypertension by activating the PPARδ/PI3K/Akt/eNOS or PPARδ/AMPK/eNOS pathway. H₂S may serve as an effective strategy against hypertension.

Aims. We object to elucidate that protective effect of H₂S on endothelium is mediated by downregulating BMP4 (bone morphogenetic protein 4)/cyclooxygenase‐ (COX‐) 2 pathway in rats with hypertension. Methods and Results. The hypertensive rat model induced by two‐kidney one‐clip (2K1C) model was used. Exogenous NaHS administration (56 μmol/kg/day, intraperitoneally once a day) reduced mean arterial pressure (MAP) of 2K1C rats from 199.9 ± 3.312 mmHg to 159.4 ± 5.434 mmHg, while NaHS did not affect the blood pressure in the Sham rats and ameliorated endothelium‐dependent contractions (EDCs) of renal artery in 2K1C rats. 2K1C reduced CSE level twofold, decreased plasma levels of H₂S about 6‐fold, increased BMP4, Nox2, and Nox4 levels 2‐fold and increased markers of oxidative stress MDA and nitrotyrosine 1.5‐fold, upregulated the expression of phosphorylation‐p38 MAPK 2‐fold, and increased protein levels of COX‐2 1.5‐fold, which were abolished by NaHS treatment. Conclusions. Our results demonstrate that H₂S prevents activation of BMP4/COX‐2 pathway in hypertension, which may be involved in the ameliorative effect of H₂S on endothelial impairment. These results throw light on endothelial protective effect of H₂S and provide new target for prevention and therapy of hypertension.

Hydrogen sulfide (H₂S) acts as an endogenous gaseous transmitter in the central nervous system and plays important roles in regulating cardiovascular function. The rostral ventrolateral medulla (RVLM) is a putative critical central region in the control of sympathetic vasomotor tone and plays an important role in the baroreflex by integrating the inputs from a variety of visceral and somatic stimuli. In this study, we tested the hypothesis that H₂S decreases sympathetic vasomotor tone through ATP-sensitive potassium channels (K_ATP) in the RVLM. The arterial blood pressure (ABP), heart rate (HR), and renal sympathetic nerve activity (RSNA) of anesthetized rats were recorded. Bilateral microinjections of sodium hydrosulfide (NaHS; 4, 8, and 16 mM, 50 nl), an H₂S donor, into the RVLM decreased ABP, HR, and RSNA in a dose-dependent manner. Preinjection of glibenclamide (40 μM, 50 nl), a K_ATP channel blocker, abolished the sympathoinhibitory effects of NaHS (8 mM, 50 nl). Preinjection of a nitric-oxide synthase inhibitor, N_ω-nitro-l-arginine methyl ester (200 μM, 50 nl) partially inhibited the sympathoinhibitory effects of NaHS. Prior microinjection of 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl]phenyl)pyridine-3-carboxylic acid methyl ester (Bay K8644) (1 μM, 50 nl), an agonist of Ca²⁺ channels, did not alter the effects of NaHS. Infusion of hydroxylamine (30 mM, 50 nl), a cystathionine β-synthase inhibitor, increased ABP, HR, and RSNA. Taken together, these findings suggest that exogenous H₂S in the RVLM inhibits sympathetic vasomotor tone by opening K_ATP channels. Nitric-oxide signaling may partially be involved in the sympathoinhibitory effect of H₂S in the RVLM.