title: The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy.
abstract: 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.
authors: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors: Miao
authors: M
authors: Lin
authors: Wai Han
authors: WH
authors: Yiu
authors: Rui Xi
authors: RX
authors: Li
authors: Hao Jia
authors: HJ
authors: Wu
authors: Dickson W L
authors: DW
authors: Wong
authors: Loretta Y Y
authors: LY
authors: Chan
authors: Joseph C K
authors: JC
authors: Leung
authors: Kar Neng
authors: KN
authors: Lai
authors: Sydney C W
authors: SC
authors: Tang
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001806:Blood Urea Nitrogen; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics; D053495:Osteopontin / Q000378:metabolism; D013311:Streptozocin; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C501717:CRX-526; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D016328:NF-kappa B; C506896:Spp1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D053495:Osteopontin; D013311:Streptozocin; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D005944:Glucosamine