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Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy.
J Am Soc Nephrol. 2012 Jan; 23(1):86-102.JA

Abstract

Inflammation contributes to the tubulointerstitial lesions of diabetic nephropathy. Toll-like receptors (TLRs) modulate immune responses and inflammatory diseases, but their role in diabetic nephropathy is not well understood. In this study, we found increased expression of TLR4 but not of TLR2 in the renal tubules of human kidneys with diabetic nephropathy compared with expression of TLR4 and TLR2 in normal kidney and in kidney disease from other causes. The intensity of tubular TLR4 expression correlated directly with interstitial macrophage infiltration and hemoglobin A1c level and inversely with estimated glomerular filtration rate. The tubules also upregulated the endogenous TLR4 ligand high-mobility group box 1 in diabetic nephropathy. In vitro, high glucose induced TLR4 expression via protein kinase C activation in a time- and dose-dependent manner, resulting in upregulation of IL-6 and chemokine (C-C motif) ligand 2 (CCL-2) expression via IκB/NF-κB activation in human proximal tubular epithelial cells. Silencing of TLR4 with small interfering RNA attenuated high glucose-induced IκB/NF-κB activation, inhibited the downstream synthesis of IL-6 and CCL-2, and impaired the ability of conditioned media from high glucose-treated proximal tubule cells to induce transmigration of mononuclear cells. We observed similar effects using a TLR4-neutralizing antibody. Finally, streptozotocin-induced diabetic and uninephrectomized TLR4-deficient mice had significantly less albuminuria, renal dysfunction, renal cortical NF-κB activation, tubular CCL-2 expression, and interstitial macrophage infiltration than wild-type animals. Taken together, these data suggest that a TLR4-mediated pathway may promote tubulointerstitial inflammation in diabetic nephropathy.

Authors+Show Affiliations

Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22021706

Citation

Lin, Miao, et al. "Toll-like Receptor 4 Promotes Tubular Inflammation in Diabetic Nephropathy." Journal of the American Society of Nephrology : JASN, vol. 23, no. 1, 2012, pp. 86-102.
Lin M, Yiu WH, Wu HJ, et al. Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):86-102.
Lin, M., Yiu, W. H., Wu, H. J., Chan, L. Y., Leung, J. C., Au, W. S., Chan, K. W., Lai, K. N., & Tang, S. C. (2012). Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. Journal of the American Society of Nephrology : JASN, 23(1), 86-102. https://doi.org/10.1681/ASN.2010111210
Lin M, et al. Toll-like Receptor 4 Promotes Tubular Inflammation in Diabetic Nephropathy. J Am Soc Nephrol. 2012;23(1):86-102. PubMed PMID: 22021706.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. AU - Lin,Miao, AU - Yiu,Wai Han, AU - Wu,Hao Jia, AU - Chan,Loretta Y Y, AU - Leung,Joseph C K, AU - Au,Wo Shing, AU - Chan,Kwok Wah, AU - Lai,Kar Neng, AU - Tang,Sydney C W, Y1 - 2011/10/21/ PY - 2011/10/25/entrez PY - 2011/10/25/pubmed PY - 2012/3/10/medline SP - 86 EP - 102 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 23 IS - 1 N2 - Inflammation contributes to the tubulointerstitial lesions of diabetic nephropathy. Toll-like receptors (TLRs) modulate immune responses and inflammatory diseases, but their role in diabetic nephropathy is not well understood. In this study, we found increased expression of TLR4 but not of TLR2 in the renal tubules of human kidneys with diabetic nephropathy compared with expression of TLR4 and TLR2 in normal kidney and in kidney disease from other causes. The intensity of tubular TLR4 expression correlated directly with interstitial macrophage infiltration and hemoglobin A1c level and inversely with estimated glomerular filtration rate. The tubules also upregulated the endogenous TLR4 ligand high-mobility group box 1 in diabetic nephropathy. In vitro, high glucose induced TLR4 expression via protein kinase C activation in a time- and dose-dependent manner, resulting in upregulation of IL-6 and chemokine (C-C motif) ligand 2 (CCL-2) expression via IκB/NF-κB activation in human proximal tubular epithelial cells. Silencing of TLR4 with small interfering RNA attenuated high glucose-induced IκB/NF-κB activation, inhibited the downstream synthesis of IL-6 and CCL-2, and impaired the ability of conditioned media from high glucose-treated proximal tubule cells to induce transmigration of mononuclear cells. We observed similar effects using a TLR4-neutralizing antibody. Finally, streptozotocin-induced diabetic and uninephrectomized TLR4-deficient mice had significantly less albuminuria, renal dysfunction, renal cortical NF-κB activation, tubular CCL-2 expression, and interstitial macrophage infiltration than wild-type animals. Taken together, these data suggest that a TLR4-mediated pathway may promote tubulointerstitial inflammation in diabetic nephropathy. SN - 1533-3450 UR - https://www.unboundmedicine.com/medline/citation/22021706/Toll_like_receptor_4_promotes_tubular_inflammation_in_diabetic_nephropathy_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=22021706 DB - PRIME DP - Unbound Medicine ER -