Open AccessTLR 4 mutant mice are protected from renal fibrosis and chronic kidney disease progression
Author(s) -
Souza Ana C. P.,
Tsuji Takayuki,
Baranova Iri.,
Bocharov Alexander V.,
Wilkins Kenneth J.,
Street Jonathan M.,
AlvarezPrats Alejandro,
Hu Xuzhen,
Eggerman Thomas,
Yuen Peter S. T.,
Star Robert A.
Publication year - 2015
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12558
Subject(s) - kidney disease , glomerulosclerosis , fibrosis , medicine , tlr4 , kidney , endocrinology , albuminuria , inflammation , immunology , proteinuria
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 TLR 4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR 4 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 ( TLR 4 WT ) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR 4 mutant mice were significantly protected from CKD progression. TLR 4 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 TLR 4 mutant mice. In vitro, endotoxin ( LPS ) directly upregulated NLRP 3 inflammasome expression in renal epithelial cells via TLR 4. In summary, TLR 4 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 .