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PODOCYTE INJURY IS SUPPRESSED BY 1,25-DIHYDROXYVITAMIN D3 VIA MODULATION OF TRANSFORMING GROWTH FACTOR-[beta]1/BONE MORPHOGENETIC PROTEIN-7 SIGNALLING IN PUROMYCIN AMINONUCLEOSIDE NEPHROPATHY RATS.
Xiao, Hou-Qin *,+,++; Shi, Wei *,++; Liu, Shuang-Xin *; Zhang, Bin *; Xu, Li-Xia *; Liang, Xin-Ling *; Liang, Yong-Zheng *
[Article] Clinical & Experimental Pharmacology & Physiology. 36(7):682-689, July 2009.

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SUMMARY:

1. Accumulating evidence suggests that vitamin D and its analogues are renoprotective. However, the precise mechanisms and the molecular targets by which active vitamin D exerts its beneficial effects remain obscure. The objective of the present study was to evaluate the effect of active vitamin D on rats with puromycin aminonucleoside (PAN) nephropathy, a model that is characterized by predominant podocyte injury.

2. The PAN nephropathy rats were created by a single intravenous injection of 100 mg/kg PAN. Changes in renal pathology and podocyte numbers were observed. Real-time polymerase chain reaction (PCR) was performed to examine mRNA expression of nephrin, transforming growth factor (TGF)-[beta]1 and bone morphogenetic protein (BMP)-7. Protein expression of nephrin, TGF-[beta]1, BMP-7 and p-Smad2/3 and p-Smad1/5/8 was examined by immunofluorescence, immunohistochemistry and western blotting, respectively. Rats were treated with 1,25(OH)2D3 by gastric gavage at a dose of 2.5 [micro]g/kg per day, starting 2 days before PAN injection and continuing throughout the experiment.

3. A single injection of PAN induced massive proteinuria and elevated serum creatinine on Day 7, both of which were significantly suppressed by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Immunofluorescence and real-time PCR of the podocyte-associated protein nephrin revealed reduced and discontinuous staining and this change was reversed by 1,25(OH)2D3. In PAN nephropathy rats, TGF-[beta]1 and p-Smad2/3 expression was upregulated, whereas that of BMP-7 and p-Smad1/5/8 was downregulated. Treatment with 1,25(OH)2D3 significantly restored BMP-7/Smad signalling while suppressing TGF-[beta]1/Smad signalling.

4. In conclusion, 1,25(OH)2D3 can ameliorate podocyte damage and proteinuria induced by PAN. The beneficial effects of 1,25(OH)2D3 on podocytes may be attributable, in part, to direct modulation of TGF-[beta]1/BMP-7 signalling.