| Summary: | <p><b>Background: </b>Selective proteinuria is frequently observed in glomerular diseases characterized by podocyte injury. Although, 1,25-dihydroxyvitamin D3 [1,25(OH)<sub>2</sub>D<sub>3</sub>] has potential therapeutic effects on chronic kidney diseases through decreasing podocyte loss, the mechanism underlying the beneficial effects of 1,25(OH)<sub>2</sub>D<sub>3</sub> on podocytes remains still unknown. The present study tested the hypothesis that 1,25(OH)<sub>2</sub>D<sub>3</sub> directly reduced podocyte apoptosis and loss.</p><p><b>Methods:</b> Sprague-Dawley (SD) rats were randomly assigned into three groups: Adriamycin (ADR) group (n=15), ADR+1,25-(OH)<sub>2</sub>D<sub>3</sub> group (n=16), and control group (n=16). Rats in ADR+1,25-(OH)<sub>2</sub>D<sub>3</sub> group were treated with 1,25(OH)<sub>2</sub>D<sub>3</sub> for 8 weeks. The number of podocytes and foot process width (FPW) were detected by transmission electron microscopy. The number of apoptotic podocytes per glomerulus and that of apoptotic nuclei and caspase-3 activity in cultured podocytes were determined by TUNEL staining. The average number of podocytes per glomerulus was quantified by immunohistochemistry. Expressions of p-Smad2/3, p-Smad1/5/8, Fas, Fas-Associated protein with Death Domain (FADD), Bax, and Bcl-2 proteins were examined by Western blot assay.</p><p><b>Results: </b>Compared with control group, proteinuria, FPW, apoptotic podocytes, caspase-3 activity, the protein expressions of p-Smad2/3, Fas, FADD, and Bax were significantly increased, podocyte density, p-Smad1/5/8 and Bcl-2 expression were decreased in ADR group. 1,25(OH)<sub>2</sub>D<sub>3</sub> significantly reduced proteinuria, FPW, caspase-3 activity, expressions of p-Smad2/3, Fas, FADD, and Bax and apoptosis of podocytes, but increased serum albumin, number of viable podocytes , p-Smad1/5/8 and Bcl-2 expression in ADR treated rats.</p><p><b>Conclusion:</b> ADR-induced podocyte apoptosis was associated with the imbalance of p-Smad2/3, p-Smad1/5/8 the activity of caspase-3 and aberrant expressions of, Fas, FADD, Bax and Bcl-2. The beneficial effects of 1,25(OH)<sub>2</sub>D<sub>3 </sub>on podocytes may be attributable to inhibit podocyte apoptosis and the amelioration of podocytopenia.</p>
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