Effect of 1,25(OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats

Abstract

In the past, there has been considerable concern that treatment with active vitamin D might accelerate progression independent of hypercalcemia and hypercalcuria. Nevertheless, 1,25(OH)2D3 has known antiproliferative 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)2D3 might even attenuate progression. To test this working hypothesis we performed two experiments of 8 and 16 weeks duration, respectively, to compare subtotally nephrectomized (SNX) rats treated with ethanol and SNX treated with 1,25(OH)2D3. Control animals were sham operated and pair-fed with SNX animals. 1,25(OH)2D3 (3 ng/100 g body wt/day) was administered by osmotic minipump. 1,25(OH)2D3 had no significant effect on systolic blood pressure and only a transient effect on weight gain. SNX reduced 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) microns 3 in sham operated animals and significantly (P < 0.05) higher (10.1 +/- 1.75 x 10(6) microns 3) in untreated animals 16 weeks after SNX. Glomerular volume was significantly (P < 0.05) less in 1,25(OH)2D3 treated SNX [10.1 +/- 1.75 in ethanol vs. 7.04 +/- 1.78 in 1,25(OH)2D3 treated SNX]. In parallel, there was significantly (P < 0.01) less glomerulosclerosis [glomerulosclerosis index 1.16 +/- 0.14 in the ethanol treated SNX vs. 0.80 +/- 0.16 in SNX treated with 1,25(OH)2D3] in the eight week experiment. Albuminuria was significantly (P < 0.01) lower in 1,25(OH)2D3 treated than in ethanol treated SNX (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 second 16 week experiment. Only slight changes of the vascular sclerosis index and tubulointerstitial index were seen in SNX and were not affected by 1,25(OH)2D3 further. To prove that the effect of 1,25(OH)2D3 was independent of PTH, parathyreoidectomized SNX rats without or with 1,25(OH)2D3 treatment were examined seven days post-SNX. PCNA staining showed suppression of cell proliferation. Furthermore, in situ hybridization for transforming growth factor-B (TGF-beta) showed less vascular and tubular expression in 1,25(OH)2D3 treated rats. We conclude that 1,25(OH)2D3 has antiproliferative actions during the compensatory growth of nephrons in response to subtotal nephrectomy. These effects are independent of PTH. The data document that 1,25(OH)2D3 reduces renal cell proliferation and glomerular growth as well as glomerulosclerosis and albuminuria as indicators of progressive glomerular damage.

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

“…A delayed and less intense rise of albumin excretion was achieved with R-568 and calcitriol, consistent with previous findings in experimental studies (17,19) and clinical observations (2).…”

“…Urinary albumin excretion was measured with a rat-specific sandwich ELISA system using the microplate technique and a rabbit anti-rat albumin peroxidase-conjugated antibody, as described in detail elsewhere (19). The blood parameters were determined in samples taken from the abdominal aorta by standard laboratory methods before the animals were killed.…”

“…The DNA sequence was cut with restriction enzymes Bcu I (for sense sequence) and Nco I (for antisense sequence; Fermentas) and linearized, and the single-chain RNA probes were synthesized with T7 (sense) or Sp6 (antisense) RNA polymerase (Roche Diagnostics) and, finally, labeled with digoxigenin. The in situ hybridization was performed as described previously in detail (19) with probe concentration of 1 ng/ l.…”

“…Moreover, beneficial effects of active vitamin D on progression of chronic kidney disease have been documented (13,19).…”

1,25-Dihydroxyvitamin D3 Ameliorates Podocytopenia in Rats with Adriamycin-induced Nephropathy

“…1,25(OH)2D3 could decrease podocyte loss and inhibit podocyte hypertrophy in SNX rats (10). 1,25(OH)2D3 could reduce proteinuria in active Thy1-nephritis rats (30) and inhibit progressive glomerulosclerosis and decrease albuminuria in SNX rats (31). Li et al (32) recently noted that 1,25(OH)2D3 was a negative endocrine regulator of the renin-angiotensin system (RAS).…”