The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy

• Published in: Kidney international Vol. 83; no. 5; pp. 887 - 900
• Main Authors: Lin, Miao, Yiu, Wai Han, Li, Rui Xi, Wu, Hao Jia, Wong, Dickson W.L., Chan, Loretta Y.Y., Leung, Joseph C.K., Lai, Kar Neng, Tang, Sydney C.W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013; Elsevier Limited
• Subjects: Albuminuria - etiology; Albuminuria - immunology; Albuminuria - prevention & control; Animals; Blood Glucose - metabolism; Blood pressure; Blood Urea Nitrogen; Chemokine CCL2 - metabolism; Chemokine CCL5 - metabolism; Collagen - metabolism; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - immunology; Diabetic Nephropathies - blood; Diabetic Nephropathies - etiology; Diabetic Nephropathies - immunology; Diabetic Nephropathies - pathology; Diabetic Nephropathies - prevention & control; diabetic nephropathy; Disease Progression; eNOS knockout mice; Glucosamine - analogs & derivatives; Glucosamine - pharmacology; HMGB1 Protein - metabolism; Kidney - drug effects; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Knockout; NF-kappa B - metabolism; Nitric Oxide Synthase Type III - deficiency; Nitric Oxide Synthase Type III - genetics; Osteopontin - metabolism; Streptozocin; Time Factors; Toll-like receptor 4; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - metabolism; Transforming Growth Factor beta - metabolism; tubulointerstitial pathology; tubulointerstitial pathology; eNOS knockout mice; diabetic nephropathy; Toll-like receptor 4
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2013.11

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-β overexpression and NF-κB activation. In vitro, CRX-526 inhibited high glucose-induced osteopontin upregulation and NF-κB 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.