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

Previous studies by us and others demonstrated that activation of Wnt/beta-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/beta-catenin signaling. Instead, decreased levels of TGF-beta1 and TGF-beta receptors (TbetaRs) 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-beta/Smad signaling. In consistent with this hypothesis, LRP5 overexpression resulted in enhanced TGF-beta/Smad signaling activation in renal tubule epithelial cells. Furthermore, LRP5 was co-immunoprecipitated with TbetaRI and TbetaRII, and its extracellular domain was essential for interacting with TbetaRs and for its pro-fibrotic activity. In addition to stabilizing TbetaRs, LRP5 increased the basal membrane presentation and TGF-beta1-induced internalization of these receptors. Notably, TGF-beta1 also induced LRP5 internalization. These findings indicate that LRP5 promotes tubulointerstitial fibrosis, at least partially, via direct modulation of TGF-beta/Smad signaling, a novel, Wnt-independent function.