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

Abstract

Recent studies implicate Wnt/β-catenin signaling in podocyte dysfunction. Because vitamin D analogs can inhibit β-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-β1, 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 β-catenin, predominantly in podocytes and tubular epithelial cells, accompanied renal injury; paricalcitol largely abolished this induction of renal β-catenin and inhibited renal expression of Snail, a downstream effector of Wnt/β-catenin signaling. Administration of paricalcitol also ameliorated established proteinuria. In vitro, paricalcitol induced a physical interaction between the vitamin D receptor and β-catenin in podocytes, which led to suppression of β-catenin-mediated gene transcription. In summary, these findings suggest that paricalcitol prevents podocyte dysfunction, proteinuria, and kidney injury in adriamycin nephropathy by inhibiting Wnt/β-catenin signaling.

• Authors: Weichun He, Young Sun Kang, Chunsun Dai, Youhua Liu
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 22 Issue 1 Pg. 90-103 (Jan 2011) ISSN: 1533-3450 [Electronic] United States
• PMID: 21030600 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ergocalciferols
• Wnt Proteins
• beta Catenin
• Vitamin D
• paricalcitol
• Doxorubicin

Topics

• Acute Kidney Injury (chemically induced, pathology, prevention & control)
• Animals
• Disease Models, Animal
• Doxorubicin (adverse effects)
• Ergocalciferols (pharmacology)
• Glomerular Mesangium (drug effects, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Podocytes (drug effects, metabolism, pathology)
• Proteinuria (prevention & control)
• Signal Transduction (drug effects, physiology)
• Vitamin D (analogs & derivatives)
• Wnt Proteins (antagonists & inhibitors, metabolism)
• beta Catenin (antagonists & inhibitors, metabolism)