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1 Department of Pathology, University of Erlangen, Erlangen, Germany
2 Department of Internal Medicine, University of Erlangen, Erlangen, Germany
3 Department of Pathology, University of Heidelberg, Heidelberg, Germany
4 Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany
5 Department of Biomedicine, University of Erlangen, Erlangen, Germany
* To whom correspondence should be addressed. E-mail: kerstin.amann{at}patho.imed.uni-erlangen.de.
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 interfered 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 SNX rats treated with non-pharmacological doses of 1,25(OH)2D3. Male Sprague-Dawley rats were sham operated (sham) or subtotally nephrectomized (SNX) under general anesthesia and received either solvent or 1,25(OH)2D3 (3ng/100g bw/day s.c.). Blood pressure (BP) and albuminuria were measured. After 16 weeks the remnant renal tissue was perfusionfixed 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. Albuminuria was significantly lower in SNX+1,25(OH)2D3 compared to SNX+solvent. Mean glomerular tuft volume was significantly higher in SNX+solvent (2.69±0.21 106µm3) than in sham (1.44±0.17 and 1.28±0.14 106 µm3); it was significantly (p<0.05) lower in SNX+1,25(OH)2D3 (1.81±0.16 106 µm3). The main finding was a significantly higher number of podocytes in SNX+1,25(OH)2D3 (88±9) and sham (98±17) as compared to SNX+solvent (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 which may also explain less pronounced albuminuria and glomerulosclerosis.
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