Sustained‐release of hydrogen sulfide by GYY4137 protected diabetic‐induced kidney injury

Abstract

Hydrogen sulfide (H2S) has been recognized as the third gaseous signaling molecule after nitric oxide and carbon monoxide. It plays an important role in regulation of physiological and pathophysiological functions in many systems including the renal system. It has been reported that sustained‐release of H2S by GYY4137 suppresses diabetes‐accelerated atherosclerosis and has protective effects on diabetic nephropathy. However, whether the increase of H2S by GYY4137 can also protect diabetic kidney disease (DKD) ‐ induce proteinuria and reduce the damages in podocytes is unknown. The diabetes mellitus mouse model was used for this study. The CD‐1 mice were intraperitoneally (ip) injected with streptozotocin (STZ) 50mg/kg for 4 days and then diabetic mice were fed with high fat diet for 12 weeks. Under this condition, the DKD was development as indicated by proteinuria and damages in podocytes in these mice. The experiments were performed in four groups, control group (without STZ), DKD miceand GYY4137 treated groups with (5mg/kg) and (20mg/kg) respectively. GYY4137 was given by daily ip injection for 12 weeks (during this period animals feeding with high fat diet). Urinary albumin concentrations, kidney morphology changes and podocytes foot process was examined by light and electron microscopes. The level of apoptosis was examined by TUNEL staining. These changes were analyzed and compared among groups. In addition, the levels of H2S in the plasma (in both human and mice) and in kidneys (mice) and the expression levels of the H2S producing enzymes, Cystyl sulfide synthetase (CBS), cystyl sulfide beta lyase (CSE) and the 3‐thiol pyruvate transferase (3‐MST) in the kidney were detected by Western blotting (WB) and immunohistochemical methods. Experimental results showed that the plasma H2S was lower in DKD patient than healthy controls (17.8 ± 2.2 vs 24.8 ± 3.6 mmol/l, P<0.01), and also in DKD mice compared with the control mice (18.7 ± 4.1 vs 40.7 ± 4.5 mmol/l, P<0.01). The H2S level was also lower in DKD mouse kidney compare with the control kidney (52.1 ± 7.2 vs 81.6 ± 14.1 nmol/g, P<0.01). WB showed the expression of CBS was reduced, but not CSE and MST in DKD kidney compare with the control. Administrations of GYY4137 significantly reduced urine albumin in DKD mice compare to the untreated group. The 24‐hour urine albumin was 46.6 ± 47.2 μg in treated and 144.6 ± 61μg in untreated group respectively (P<0.05). Although the blood glucose levels were the same in both treated and untreated groups (30 ± 4.2 vs. 31.8 ± 2.1 mmol/l, P>0.05), GYY4137 reduced both the mesangial hyperplasia and fusion of foot process in DKD kidney, indicating less damage of mesangia cells and the podocytes. GYY4137 also reduced DKD increased apoptosis in the kidney, detected by TUNEL staining in renal tissue. Our study shown that sustained‐release of H2S by GYY4137 decreases the urinary albumin and reduces kidney tissue apoptosis, mesangial proliferation and foot process infusion in DKD mice, thus indicating that H2S has significant protective effects on DKD.Support or Funding InformationNIH/NIDDK RO1 DK099284 and P01 DK 17433This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.