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Departments of 1Pathology and 2Internal Medicine, 5Institute of Biomedicine, Universitiy of Erlangen-Nuernberg, D-91054 Erlangen; and Departments of 3Pathology and 4Internal Medicine, University of Heidelberg, 69115 Heidelberg, Germany
Submitted 3 September 2003 ; accepted in final form 26 October 2003
1,25(OH)2D3 has antiproliferative effects and promotes cell differentiation. This consideration has provided the rationale for studies in subtotally nephrectomized rats showing that 1,25(OH)2D3 interferred 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-1 sc). 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)2D3 compared with SNX+solvent rats. Mean glomerular tuft volume was significantly higher in SNX+solvent (2.69 ± 0.21 gx 106 µm3) than in sham rats (1.44 ± 0.17 and 1.28 ± 0.14 x 106 µm3); it was significantly (P < 0.05) lower in SNX+1,25(OH)2D3 rats (1.81 ± 0.16 x 106 µm3). 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.
visceral glomerular epithelial cell; mesangial cell; glomerular endothelial cell; progression
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