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Abstract: SA-PO220

Bone Marrow-Derived C5aR Contributes to Kidney Inflammation and Tubulointerstitial Fibrosis in Streptozotocin (STZ)-Induced Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ma, Jingyuan, The University of Hong Kong, Hong Kong, Hong Kong
  • Yiu, Wai Han, The University of Hong Kong, Hong Kong, Hong Kong
  • Lok, Sarah W.Y., The University of Hong Kong, Hong Kong, Hong Kong
  • Zou, Yixin, The University of Hong Kong, Hong Kong, Hong Kong
  • Chan, Loretta Y.Y., The University of Hong Kong, Hong Kong, Hong Kong
  • Tang, Sydney C.W., The University of Hong Kong, Hong Kong, Hong Kong
Background

Emerging evidence shows a pathogenic role of C5a in the progression of diabetic nephropathy (DN). However, the contribution of C5aR signaling from circulating leukocytes and resident kidney cells to the progression of DN has not yet been investigated.

Methods

Bone marrow chimeras were generated by transplanting GFP-expressing bone marrow cells from donor mice (GFP-C5aR+/+ WT or GFP-C5aR-/- KO) into irradiated recipient mice (C5aR+/+ WT or C5aR-/- KO) via intravenous injection. They were: 1) GFP-C5aR+/+ to C5aR+/+ (WTWT), 2) GFP-C5aR+/+ to C5aR-/- KO (WTKO), 3) GFP-C5aR-/- to C5aR+/+ (KOWT) and 4) GFP-C5aR-/- to C5aR-/- (KO→KO). Peripheral blood and bone marrow samples from the chimeras were used for engraftment analysis by flow cytometry. Six weeks after transplantation, all chimeric mice were subjected to low-dose (50 mg/kg; 5 consecutive days) streptozotocin (STZ)-induced diabetes for 12 weeks. Blood samples and kidneys were harvested for determination of kidney function, inflammation and fibrosis.

Results

Chimerism was confirmed with more than 97% of bone marrow cells and 95% of circulating CD45+ cells being GFP positive. At 12 weeks after STZ injection, blood glucose levels were significantly increased which were not different among all diabetic groups. Serum creatinine in diabetic WT→WT recipients was elevated while that from diabetic WT→KO, KO→WT and KO→KO recipients was lower. Kidney expression levels of MCP-1, TNF- α and fibronectin were also significantly increased in diabetic WT→WT recipients, but they were only suppressed in the diabetic KO→WT and KO→KO groups.

Conclusion

Diabetic chimeric mice reconstituted with C5aR-/- bone marrow cells were protected from kidney inflammation and fibrosis, suggesting that C5aR signaling in bone marrow-derived cells is a key driver in STZ-induced DN.
Funding: National Natural Science Foundation of China (grant number: 81870496); Mr & Mrs Tam Wing Fan Edmund Renal Research Fund