1,25-Dihydroxyvitamin D3decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat

Abstract

1,25(OH)₂D₃has antiproliferative effects and promotes cell differentiation. This consideration has provided the rationale for studies in subtotally nephrectomized rats showing that 1,25(OH)₂D₃interferred with glomerulosclerosis. The cellular mechanisms involved have remained obscure, however. It was the purpose of the present study to assess glomerular structure and cellular composition in subtotally nephrectomized (SNX) rats treated with nonpharmacological doses of 1,25(OH)₂D₃. Male Sprague-Dawley rats were sham operated (sham) or underwent SNX under general anesthesia and received either solvent or 1,25(OH)₂D₃(3 ng·100 g body wt^-1·day^-1sc). Blood pressure (BP) and albuminuria were measured. After 16 wk, the remnant renal tissue was perfusion fixed and morphometric and stereological measurements were carried out. The expression of proliferating cellular antigen (PCNA), cyclin-dependent kinase inhibitor p27, Wilms tumor gene (WT1), and desmin, a marker of early podocyte damage, was investigated by immunohistology. BP, serum creatinine, and urinary albumin excretion were significantly higher in SNX than in sham rats. Albuminuria was significantly lower in SNX+1,25(OH)₂D₃compared with SNX+solvent rats. Mean glomerular tuft volume was significantly higher in SNX+solvent (2.69 ± 0.21 g× 10⁶μm³) than in sham rats (1.44 ± 0.17 and 1.28 ± 0.14 × 10⁶μm³); it was significantly ( P < 0.05) lower in SNX+1,25(OH)₂D₃rats (1.81 ± 0.16 × 10⁶μm³). The main finding was a significantly higher number of podocytes in SNX+1,25(OH)₂D₃(88 ± 9) and sham (98 ± 17) compared with SNX+solvent rats (81 ± 8.7). In parallel, the increase in podocyte volume in SNX+solvent rats was abrogated by treatment with 1,25(OH)₂D₃, and immunohistochemistry revealed less expression of desmin, PCNA, and p27, suggesting less podocyte injury and activation of the cyclin cascade. This study identifies the podocyte as an important target cell for the renoprotective action of 1,25(OH)₂D₃. This notion is suggested by less evidence of podocyte injury, decreased podocytes loss, and abrogation of podocyte hypertrophy, findings that may also explain less pronounced albuminuria and glomerulosclerosis.