The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy

Miao Lin, Wai Han Yiu, Rui Xi Li, Hao Jia Wu, Dickson W.L. Wong, Loretta Y.Y. Chan, Joseph C.K. Leung, Kar Neng Lai, Sydney C.W. Tang

Research output: Contribution to journalArticle

76 Scopus citations

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.

Original languageEnglish
Pages (from-to)887-900
Number of pages14
JournalKidney International
Volume83
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

Keywords

  • Toll-like receptor 4
  • diabetic nephropathy
  • eNOS knockout mice
  • tubulointerstitial pathology

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    Lin, M., Yiu, W. H., Li, R. X., Wu, H. J., Wong, D. W. L., Chan, L. Y. Y., Leung, J. C. K., Lai, K. N., & Tang, S. C. W. (2013). The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney International, 83(5), 887-900. https://doi.org/10.1038/ki.2013.11