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A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-?/Smad signaling.


ABSTRACT: Previous studies by us and others demonstrated that activation of Wnt/?-catenin signaling plays a pathogenic role in chronic kidney diseases (CKD). Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease; but their exact roles in this disease and renal fibrosis have not been explored. Here, we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model. In the obstructed kidneys, Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and tubular injury without changing Wnt/?-catenin signaling. Instead, decreased levels of TGF-?1 and TGF-? receptors (T?Rs) were detected in Lrp5 knockout kidneys, followed by attenuated activation and nuclear translocation of Smad2/3 in the renal tubules, suggesting a regulatory effect of LRP5 on TGF-?/Smad signaling. In consistent with this hypothesis, LRP5 overexpression resulted in enhanced TGF-?/Smad signaling activation in renal tubule epithelial cells. Furthermore, LRP5 was co-immunoprecipitated with T?RI and T?RII, and its extracellular domain was essential for interacting with T?Rs and for its pro-fibrotic activity. In addition to stabilizing T?Rs, LRP5 increased the basal membrane presentation and TGF-?1-induced internalization of these receptors. Notably, TGF-?1 also induced LRP5 internalization. These findings indicate that LRP5 promotes tubulointerstitial fibrosis, at least partially, via direct modulation of TGF-?/Smad signaling, a novel, Wnt-independent function.

SUBMITTER: He X 

PROVIDER: S-EPMC7188863 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-β/Smad signaling.

He Xuemin X   Cheng Rui R   Huang Chao C   Takahashi Yusuke Y   Yang Yanhui Y   Benyajati Siribhinya S   Chen Yanming Y   Zhang Xin A XA   Ma Jian-Xing JX  

Signal transduction and targeted therapy 20200429 1


Previous studies by us and others demonstrated that activation of Wnt/β-catenin signaling plays a pathogenic role in chronic kidney diseases (CKD). Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease; but their exact roles in this disease and renal fibrosis have not been explored. Here, we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model. In the obstructed  ...[more]

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