Dataset Information

Hydrogen sulfide prevents arterial medial calcification in rats with diabetic nephropathy.

ABSTRACT:

Background

Arterial medial calcification (AMC) is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes and chronic kidney disease. Here, we tested whether hydrogen sulfide (H₂S) can prevent AMC in rats with diabetic nephropathy (DN).

Methods

DN was induced by a single injection of streptozotocin and high-fat diet (45% kcal as fat) containing 0.75% adenine in Sprague-Dawley rats for 8 weeks.

Results

Rats with DN displayed obvious calcification in aorta, and this was significantly alleviated by Sodium Hydrosulfide (NaHS, a H₂S donor, 50 μmol/kg/day for 8 weeks) treatment through decreasing calcium and phosphorus content, ALP activity and calcium deposition in aorta. Interestingly, the main endogenous H₂S generating enzyme activity and protein expression of cystathionine-γ-lyase (CSE) were largely reduced in the arterial wall of DN rats. Exogenous NaHS treatment restored CSE activity and its expression, inhibited aortic osteogenic transformation by upregulating phenotypic markers of smooth muscle cells SMα-actin and SM22α, and downregulating core binding factor α-1 (Cbfα-1, a key factor for bone formation), protein expressions in rats with DN when compared to the control group. NaHS administration also significantly reduced Stat3 activation, cathepsin S (CAS) activity and TGF-β1 protein level, and improved aortic elastin expression.

Conclusions

H₂S may have a clinical significance for treating AMC in people with DN by reducing Stat3 activation, CAS activity, TGF-β1 level and increasing local elastin level.

SUBMITTER: Wang FZ

PROVIDER: S-EPMC8515673 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Hydrogen sulfide prevents arterial medial calcification in rats with diabetic nephropathy.

Wang Fang-Zheng FZ Zhou Hong H Wang Hong-Yu HY Dai Hang-Bing HB Gao Qing Q Qian Pei P Zhou Ye-Bo YB

BMC cardiovascular disorders 20211013 1

<h4>Background</h4>Arterial medial calcification (AMC) is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes and chronic kidney disease. Here, we tested whether hydrogen sulfide (H<sub>2</sub>S) can prevent AMC in rats with diabetic nephropathy (DN).<h4>Methods</h4>DN was induced by a single injection of streptozotocin and high-fat diet (45% kcal as fat) containing 0.75% adenine in Sprague-Dawley rats for 8 weeks.<h4>Results</h4>Rats with DN displayed obviou ...[more]

PMID: 34645391

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Project description:Pathologic calcification (PC) is a painful and disabling condition whereby calcium-containing crystals deposit in tissues that do not physiologically calcify: cartilage, tendons, muscle, vessels and skin. In cartilage, compression and inflammation triggered by PC leads to cartilage degradation typical of osteoarthritis (OA). The PC process is poorly understood and treatments able to target the underlying mechanisms of the disease are lacking. Here we show a crucial role of the gasotransmitter hydrogen sulfide (H2S) and, in particular, of the H2S-producing enzyme cystathionine γ-lyase (CSE), in regulating PC in cartilage. Cse deficiency (Cse KO mice) exacerbated calcification in both surgically-induced (menisectomy) and spontaneous (aging) murine models of cartilage PC, and augmented PC was closely associated with cartilage degradation (OA). On the contrary, Cse overexpression (Cse tg mice) protected from these features. In vitro, Cse KO chondrocytes showed increased calcification, potentially via enhanced alkaline phosphatase (Alpl) expression and activity and increased IL-6 production. The opposite results were obtained in Cse tg chondrocytes. In cartilage samples from patients with OA, CSE expression inversely correlated with the degree of tissue calcification and disease severity. Increased cartilage degradation in murine and human tissues lacking or expressing low CSE levels may be accounted for by dysregulated catabolism. We found higher levels of matrix-degrading metalloproteases Mmp-3 and -13 in Cse KO chondrocytes, whereas the opposite results were obtained in Cse tg cells. Finally, by high-throughput screening, we identified a novel small molecule CSE positive allosteric modulator (PAM), and demonstrated that it was able to increase cellular H2S production, and decrease murine and human chondrocyte calcification and IL-6 secretion. Together, these data implicate impaired CSE-dependent H2S production by chondrocytes in the etiology of cartilage PC and worsening of secondary outcomes (OA). In this context, enhancing CSE expression and/or activity in chondrocytes could represent a potential strategy to inhibit PC.

Dataset Information

Hydrogen sulfide prevents arterial medial calcification in rats with diabetic nephropathy.

Background

Methods

Results

Conclusions

Publications

Hydrogen sulfide prevents arterial medial calcification in rats with diabetic nephropathy.

Similar Datasets

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