Blockade of Wnt/?-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury.

ABSTRACT: Recent studies implicate Wnt/?-catenin signaling in podocyte dysfunction. Because vitamin D analogs can inhibit ?-catenin in other tissues, we tested whether the vitamin D analog paricalcitol could ameliorate podocyte injury, proteinuria, and renal fibrosis in adriamycin (ADR) nephropathy. Compared with vehicle-treated controls, paricalcitol preserved expression of nephrin, podocin, and WT1; prevented proteinuria; and reduced glomerulosclerotic lesions induced by ADR. Paricalcitol also inhibited expression of proinflammatory cytokines, reduced renal infiltration of monocytes/macrophages, hampered activation of renal myofibroblasts, and suppressed expression of the fibrogenic TGF-?1, CTGF, fibronectin, and types I and III collagen. Selective suppression of renal Wnt4, Wnt7a, Wnt7b, and Wnt10a expression after ADR accompanied these renoprotective effects of paricalcitol. Significant upregulation of ?-catenin, predominantly in podocytes and tubular epithelial cells, accompanied renal injury; paricalcitol largely abolished this induction of renal ?-catenin and inhibited renal expression of Snail, a downstream effector of Wnt/?-catenin signaling. Administration of paricalcitol also ameliorated established proteinuria. In vitro, paricalcitol induced a physical interaction between the vitamin D receptor and ?-catenin in podocytes, which led to suppression of ?-catenin-mediated gene transcription. In summary, these findings suggest that paricalcitol prevents podocyte dysfunction, proteinuria, and kidney injury in adriamycin nephropathy by inhibiting Wnt/?-catenin signaling.

SUBMITTER: He W 

PROVIDER: S-EPMC3014038 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature