期刊
KIDNEY INTERNATIONAL
卷 83, 期 5, 页码 887-900出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2013.11
关键词
diabetic nephropathy; eNOS knockout mice; Toll-like receptor 4; tubulointerstitial pathology
资金
- Research Grants Council of Hong Kong [HKU 777009M]
- National Basic Research Program of China 973 program [2012CB517600, 2012CB517601]
- National Natural Science Foundation of China [81200538]
- Endowment Fund
- Hong Kong Concrete
- Continental Cement and Gypsum Co. Ltd.
We recently showed that Toll-like receptor (TLR) TLR4 was overexpressed in the human diabetic kidney, which could promote tubular inflammation. Here we explored whether the TLR4 antagonist, CRX-526, has therapeutic potential to attenuate renal injuries and slow the progression of advanced diabetic nephropathy in wild-type and endothelial nitric oxide synthase (eNOS) knockout mice. In the latter, the endogenous TLR4 ligand, high-mobility group box 1, was upregulated more than in wild-type animals. Four weeks after streptozotocin induction of diabetes, mice were injected with either CRX-526 or vehicle for 8 weeks. CRX-526 significantly reduced albuminuria and blood urea nitrogen without altering blood glucose and systolic blood pressure in diabetic mice. Glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial injury were attenuated by CRX-526, which was associated with decreased chemokine (C-C motif) ligand (CCL)-2, osteopontin, CCL-5 overexpression, subsequent macrophage infiltration, and collagen deposition. These effects were associated with inhibition of TGF-beta overexpression and NF-kappa B activation. In vitro, CRX-526 inhibited high glucose-induced osteopontin upregulation and NF-kappa B nuclear translocation in cultured human proximal tubular epithelial cells. Thus, we provided evidence that inhibition of TLR4 with the synthetic antagonist CRX-526 conferred renoprotective effects in eNOS knockout diabetic mice with advanced diabetic nephropathy.
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