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Abstract: PO0904

The Decrease in Renal Cystathionine β-Synthase/Hydrogen Sulfide Was Involved in the Pathogenesis of Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Yu, Yanting, Department of Nephrology,BenQ Medical Center, The Affiliated BenQ hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Ren, Zhiyun, The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Zhu, Gangyi, The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Wang, Weiwan, The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Jia, Yutao, Department of Nephrology,BenQ Medical Center, The Affiliated BenQ hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Wang, Xiaoyan, The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ hospital of Nanjing Medical University, Nanjing, Jiangsu, China

Group or Team Name

  • The Affiliated BenQ hospital of Nanjing Medical University
Background

Hydrogen sulfide (H2S) and its producing enzymes are associated with human diseases including coronary heart disease, Alzheimer's disease, diabetic retinopathy and obstructive kidney disease, etc.

Methods

In order to determine their roles in pathogenesis of diabetic nephropathy, we examined plasma H2S levels in diabetic nephropathy patients and mice, renal H2S production & H2S producing enzymes in the mouse model, and the effects of glucose on H2S producing enzymes, mainly Cystathionine β-synthase(CBS), in cultured mouse proximal convoluted tubule cells (mPTC).

Results

Plasma H2S levels were decreased in patients (17.8±0.5 vs 24.8±0.8 umol/l, p<0.05, n=18/group) and mice(18.7±1.6 vs 40.7±1.8 umol/l,p<0.05,n=6/group). The renal H2S production in mice was decreased ( vs 52.1±2.9 vs 81.5±5.8 umol/l, p<0.01) along with the reduction of renal protein expression of CBS (52.1±13.4,% of control) . A similar protein decrease of CBS(52.5±12.2, p<0.01) was found in cultured mPTC sitimulating by high glucose (25mmol/l D-glucose) , but not CSE or MST. CBS protein expression was correlated negatively with glucose concentration (0,5,10,15,20,25,mM) ( p<0.01). The significant decrease of CBS by glucose occurred at 1 , 2, 24 and 48 hrs. Ubiquitination of CBS was increased remarkably (588.7± 140, p<0.05) within 1 hr of high glucose stimulation. CBS immunostaining became less strong with high glucose at the time points of 1hr & 2hr while the co-staining of CBS and LAMP2, a lysosome marker, reached the maximum at 30 min. The decrease of CBS mRNA expression was also found at points of 6 hr, 12hr.High glucose increased nitrotyrosine(NT) (170.6±22.9, p<0.05) in mPTC, which was restored by GYY4137, a slow-releasing H2S donor. The expression of NT was increased by inhibition of CBS protein with its siRNA but was reversed by GYY4137 in normal glucose medium. Furthermore, in diabetic nephropathy mice, the urine albumin(58.6±6.6 vs 117.6±8.6 ug/d, p<0.01),mesangial matrix proliferation and glomerular basement membrane thickening were ameliorated by exogenous supplement GYY4137 at 20mg/kg for 8 weeks.

Conclusion

These findings suggest that high glucose may decrease renal CBS protein by increasing its ubiquitination/ degradation and inhibiting its mRNA, eventually induce proximal tubular cell injury due to loss of protective mechanism of H2S.

Funding

  • Government Support - Non-U.S.