Kidney Week

Abstract: TH-PO015

Complement C5a Moderates Renal Lipid Metabolism and Fibrosis in Diabetic Nephropathy

Session Information

• Complement Your Knowledge of Kidney Disease
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Diabetes

• 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

• Yiu, Wai Han, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Wai Han Yiu,

• Li, Ruixi, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Ruixi Li,

• Wong, Dickson WL, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Dickson WL Wong,

• Wu, Haojia, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Haojia Wu,

• Chan, Kam wa, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Kam wa Chan,

• Chan, Loretta Y.Y., The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Loretta Y.Y. Chan,

• Leung, Joseph C K, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Joseph C K Leung,

• Lai, Kar Neng, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Kar Neng Lai,

• Sacks, Steven H., King's College London, Guy's Hospital, London, United Kingdom

Steven H. Sacks,

• Zhou, Wuding, King's College London, Guy's Hospital, London, United Kingdom

Wuding Zhou,

• Tang, Sydney C.W., The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Sydney C.W. Tang,

Background

Complement C5 activation has been implicated in tubulointerstitial injury with increased levels of tubular C5a in renal biopsies from patients with diabetic nephropathy. We investigated whether administration of a C5a inhibitor would confer protection against the progression of diabetic nephropathy in an animal model of type 2 diabetes.

Methods

Uninephrectomized diabetic db/db mice were administrated with novel C5a inhibitor, NOX-D21 (10 mg/kg, a kind gift from NOXXON) or an equal volume of saline for a total of 12 weeks. Non-diabetic db/m mice were used as control.

Results

In db/db mice, treatment with NOX-D21 for 12 weeks did not affect hyperglycemia, but significantly prevented the increase in serum creatinine and BUN levels. These NOX-D21 treated mice had reduced glomerulosclerosis and tubular damage compared to the vehicle-treated diabetic mice. In addition, blockade of C5 signaling reduced the overexpression of TGF-β1, activation of Akt signaling and interstitial expression of fibronectin and collagen type I in the diabetic kidney. NOX-D21 also ameliorated lipid abnormalities in db/db mice and resulted in significant decrease in serum triglycerides and expression of lipid metabolism-related genes (DAGT1 and SREBP-1) in the diabetic kidney.

Conclusion

Our findings suggest a pathogenic role of C5a in diabetic nephropathy, especially in regulating TGF-β-driven renal fibrosis. Inhibition of C5a signaling partially improves renal function and ameliorates dyslipidemia in diabetic animals.

Funding: Hong Kong Society of Nephrology and Hong Kong Kidney Foundation Research Grant (2016).