Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX ϩ R-568, SNX ϩ calcitriol, SNX ϩ vehicle, sham-op ϩ R-568, sham-op ϩ calcitriol, and sham-op ϩ vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum-and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 Ϯ 1.46 vs. 2.70 Ϯ 0.91 mm 3 ), podocyte volume (831 Ϯ 127 vs. 397 Ϯ 67 m 3 ), the degree of foot process fusion (mean width of foot processes ϭ 958 Ϯ 364 vs. 272 Ϯ 35 nm), and glomerular basement membrane thickness (244 Ϯ 6 vs. 267 Ϯ 23 nm), as well as desmin staining, were significantly higher in vehicletreated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage. secondary hyperparathyroidism; chronic renal failure; nephroprotection; calcimimetics; calcitriol SECONDARY HYPERPARATHYROIDISM (sHPT) is a common feature of chronic kidney disease. Parathyroid hormone (PTH) concentrations increase progressively with diminishing glomerular filtration rate, but it is unclear whether PTH per se modifies progression.Active metabolites of vitamin D are widely used to control sHPT. Moreover, beneficial effects of active vitamin D on progression of chronic kidney disease have been documented (13,19).A therapeutic alternative is the use of calcimimetics (R-568 and, in humans, cinacalcet HCl), allosteric activators of the calcium-sensing receptor (CaSR), which reduce PTH secretion and interfere with parathyroid hyperplasia (4,20,22). In addition, however, Ogata et al. (17) showed that short-term treatment with R-568 reduces albuminuria and attenuates glomerular and tubulointerstitial lesions in subtotally nephrectomized (SNX) rats.The present study was designed to compare the effect of the two interventions on albuminuria and morphological lesions of the kidney in the SNX rat. The readouts were morphology and ultrastructure of podocytes, glomerulosclerosis index (GSI), and tubulointerstitial damage index, as well as expression profile of TGF-␤1, endothelin-1 (ET-1), and VEGF using immunohistochemistry a...

Piecha G, Koleganova N, Gross M-L, Geldyyev A, Adamczak M, Ritz E. Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination. Am J Physiol Renal Physiol 295: F137-F144, 2008. First published April 23, 2008 doi:10.1152/ajprenal.00065.2008.-Angiotensin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin II. The purpose of this study was to assess the relative ability of an angiotensin receptor type 1 (AT1) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 in the vehicle-and dihydralazine-treated groups but was significantly lowered in the SNXϩlosartan as well as in the SNXϩlosartanϩspironolactone groups and had not progressed further in the SNXϩspironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats after high-dose AT1 receptor blockade. Nonhyperkalemic doses of spironolactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the AT1 blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis. aldosterone escape; renin-angiotensin system GLOMERULOSCLEROSIS AND INTERSTITIAL fibrosis tend to progress over time even if the primary insult to the kidney is no longer operative (11). Blocking the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT 1 ) blockers slows progression in various experimental models and in patients with chronic kidney disease (11). In humans the possibility to reverse established glomerular lesions was clearly demonstrated in diabetic nephropathy after isolated pancreatic transplantation (7). In the renal ablation model in the rat, reversal of glomerulosclerosis was seen after administration of high-dose ACE inhibitors or AT 1 blockers (2,8,16). In this model, aldosterone accelerated progression of glomerulosclerosis independently of ANG II (10, 13). This finding is clinically relevant because frequently, during prolonged treatment with ACE-inhibitors or AT 1 blockers, "aldosterone breakthrou...

Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/- mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE-/- mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 μg/kg) or paricalcitol (0.1 μg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 μm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P < 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-β1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-β expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).

Background. Cinacalcet (CIN) efficiently suppresses parathyroid hormone (PTH) secretion by the activation of the calcium-sensing receptor (CaR). Epiphyseal chondrocytes also express the CaR and its activation promotes cell proliferation and differentiation in vitro. Hence, the impact of CIN on the growth plate function requires assessment before routine administration in children. Methods. We treated subtotally nephrectomized (SNX) and sham-operated, ad lib and pair-fed Sprague-Dawley rats with CIN (15 mg/kg day) or solvent (S) for 14 days p.o. and assessed whole body and tibia length gain, growth plate morphology, osseous front advance (OFA) (calcein staining) and chondrocyte proliferation rate [5-bromo-2 -deoxyuridine (BrdU) staining]. Results. Total body length gain did not differ after 7 and 14 days (SNX + CIN 2.9 ± 0.6, SNX + S 3.0 ± 0.7; sham + CIN 4.2 ± 0.4, sham + S 4.5 ± 0.4; sham pair-fed + CIN 3.3 ± 0.5, sham pair-fed + S 3.5 ± 0.6 cm/14 days; P = n.s.). Tibia length, the height of the total growth plate and the hypertrophic zone, OFA and chondrocyte proliferation rate were similar with CIN and S. Serum Ca 2+ declined with CIN treatment; PTH was 61% lower in CIN-compared to S-treated SNX (P < 0.05). Food intake was similar, whereas body weight gain (21.6 ± 8.7 versus 12.7 ± 11.2 g) and body weight gain per food intake (141 ± 50 versus 77 ± 70 g/kg) improved in CIN-versus S-treated SNX animals (P < 0.05). Conclusion. CIN treatment does not impact on growth plate chondrocyte function in uraemic rats, but improves food efficiency and body weight gain.

We conclude that in the apolipoprotein E -/- mouse, even minor reduction in renal function, for example, by uninephrectomy, causes remodeling of the heart. This was ameliorated to a similar extent by antioxidants and angiotensin-converting enzyme inhibition.