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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Albuminuria / etiology
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Albuminuria / immunology
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Albuminuria / prevention & control
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Animals
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Blood Glucose / metabolism
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Blood Urea Nitrogen
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Chemokine CCL2 / metabolism
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Chemokine CCL5 / metabolism
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Collagen / metabolism
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Diabetes Mellitus, Experimental / blood
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Diabetes Mellitus, Experimental / chemically induced
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Diabetes Mellitus, Experimental / complications
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Experimental / immunology
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Diabetic Nephropathies / blood
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Diabetic Nephropathies / etiology
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Diabetic Nephropathies / immunology
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Diabetic Nephropathies / pathology
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Diabetic Nephropathies / prevention & control*
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Disease Progression
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Glucosamine / analogs & derivatives*
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Glucosamine / pharmacology
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HMGB1 Protein / metabolism
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Kidney / drug effects*
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Kidney / immunology
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Kidney / metabolism
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Kidney / pathology
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Knockout
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NF-kappa B / metabolism
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Nitric Oxide Synthase Type III / deficiency
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Nitric Oxide Synthase Type III / genetics
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Osteopontin / metabolism
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Streptozocin
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Time Factors
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Toll-Like Receptor 4 / antagonists & inhibitors*
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Toll-Like Receptor 4 / metabolism
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Transforming Growth Factor beta / metabolism
Substances
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Blood Glucose
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CRX-526
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Ccl2 protein, mouse
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Ccl5 protein, mouse
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Chemokine CCL2
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Chemokine CCL5
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HMGB1 Protein
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HMGB1 protein, mouse
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NF-kappa B
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Spp1 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Transforming Growth Factor beta
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Osteopontin
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Streptozocin
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Collagen
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Nitric Oxide Synthase Type III
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Nos3 protein, mouse
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Glucosamine