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Physiol Rep. 2015 Sep;3(9). pii: e12558. doi: 10.14814/phy2.12558.

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression.

Author information

1
Renal Diagnostics and Therapeutics Unit, NIDDK NIH, Bethesda, Maryland.
2
Department of Laboratory Medicine, Clinical Center NIH, Bethesda, Maryland.
3
Biostatistics Program, Office of Director, NIDDK NIH, Bethesda, Maryland.
4
Department of Laboratory Medicine, Clinical Center NIH, Bethesda, Maryland Division of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK NIH, Bethesda, Maryland.
5
Renal Diagnostics and Therapeutics Unit, NIDDK NIH, Bethesda, Maryland starr@niddk.nih.gov.

Abstract

Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild-type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low-dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low-grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD.

KEYWORDS:

Albuminuria; endotoxemia; inflammasome; inflammation; spleen apoptosis

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