EFFECT OF 1,25(OH)(2) VITAMIN-D-3 ON GLOMERULOSCLEROSIS IN SUBTOTALLYNEPHRECTOMIZED RATS

In the past, there has been considerable concern that treatment with a ctive vitamin D might accelerate progression independent of hypercalce mia and hypercalcuria. Nevertheless, 1,25(OH)(2)D-3 has known antiprol iferative properties and has also been shown to inhibit renal growth. Since glomerular growth is a permissive factor for the development of glomerulosclerosis, we reasoned that 1,25(OH)(2)D-3 might even attenua te progression. To test this working hypothesis we performed two exper iments of 8 and 16 weeks duration, respectively, to compare subtotally nephrectomized (SNX) rats treated with ethanol and SNX treated with 1 ,25(OH)(2)D-3. Control animals were sham operated and pair-fed with SN X animals. 1,25(OH)(2)D-3 (3 ng/100 g body wt/day) was administered by osmotic minipump. 1,25(OH)(2)D-3 had no significant effect on systoli c blood pressure and only a transient effect on weight gain. SNX reduc ed the number of glomeruli (left kidney) from an average of 3.3 x 10(4 ) to 1.2 x 10(4) per kidney. Mean glomerular volume was 3.87 +/- 0.71 x 10(6) mu m(3) in sham operated animals and significantly (P < 0.05) higher (10.1 +/- 1.75 x 10(6) mu m(3)) in untreated animals 16 weeks a fter SNX. Glomerular volume was significantly (P < 0.05) less in 1,25( OH)(2)D-3 treated SNX [10.1 +/- 1.75 in ethanol vs. 7.04 +/- 1.78 in 1 ,25(OH)(2)D-3 treated SNX]. In parallel, there was significantly (P < 0.01) less glomerulosclerosis [glomerulosclerosis index 1.16 +/- 0.14 in the ethanol treated SMI vs. 0.80 +/- 0.16 in SNX treated with 1,25( OH)(2)D-3] in the eight week experiment. Albuminuria was significantly (P < 0.01) lower in 1,25(OH)(2)D-3 treated than in ethanol treated SN X (mean 0.785 mg/24 hr, range 0.43 to 1.80, vs. 3.75 mg/24 hr, 1.29 to 14.2). The morphological data were directionally analogous in a secon d 16 week experiment. Only slight changes of the vascular sclerosis in dex and tubulointerstitial index were seen in SNX and were not affecte d by 1,25(OH)(2)D-3 further. To prove that the effect of 1.25(OH)(2)D- 3 was independent of PTH, parathyreoidectomized SNX rats without or wi th 1,25(OH)(2)D-3 treatment were examined seven days post-SNX. PCNA st aining showed suppression of cell proliferation. Furthermore, irt situ hybridization for transforming growth factor-B (TGF-beta) showed less vascular and tubular expression in 1,25(OH)(2)D-3 treated rats. We co nclude that 1,25(OH)(2)D-3 has antiproliferative actions during the co mpensatory growth of nephrons in response to subtotal nephrectomy. The se effects are independent of PTH. The data document that 1,25(OH)(2)D -3 reduces renal cell proliferation and glomerular growth as well as g lomerulosclerosis and albuminuria as indicators of progressive glomeru lar damage.