Journal
SIGNAL TRANSDUCTION AND TARGETED THERAPY
Volume 5, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41392-020-0142-x
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Funding
- Oklahoma Center for the Advancement of Science and Technology [HR16-041]
- NIH [EY012231, EY018659, EY028949, EY019309, GM122744]
- National Nature Science Foundation of China [81700631]
- Science & Technology Development Fund of Tianjin Education Commission for Higher Education [2016YD05]
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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-beta 1 and TGF-beta receptors (T beta 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-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 T beta RI and T beta RII, and its extracellular domain was essential for interacting with T beta Rs and for its pro-fibrotic activity. In addition to stabilizing T beta Rs, LRP5 increased the basal membrane presentation and TGF-beta 1-induced internalization of these receptors. Notably, TGF-beta 1 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.
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