crx-526 and Diabetic-Nephropathies

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.

Topics: Albuminuria; Animals; Blood Glucose; Blood Urea Nitrogen; Chemokine CCL2; Chemokine CCL5; Collagen; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Progression; Glucosamine; HMGB1 Protein; Kidney; Macrophages; Mice; Mice, Knockout; NF-kappa B; Nitric Oxide Synthase Type III; Osteopontin; Streptozocin; Time Factors; Toll-Like Receptor 4; Transforming Growth Factor beta