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1 Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, Heidelberg, 69120, Germany; Department of Internal Medicine, Division Nephrology, University of Heidelberg, Heidelberg, Germany; Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland
2 Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, Heidelberg, 69120, Germany; Department of Pathophysiology, Semmelweis University, Budapest, Budapest, Hungary
3 University Children's Hospital, University of Heidelberg, Heidelberg, Germany
4 Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, Heidelberg, 69120, Germany; Department of Internal Medicine, Division Nephrology, University of Heidelberg, Heidelberg, Germany
5 Institute of Pathology, University of Heidelberg, Heidelberg, Germany
6 Department of Internal Medicine, Division Nephrology, University of Heidelberg, Heidelberg, Germany
* To whom correspondence should be addressed. E-mail: g.piecha{at}gmx.de.
Patients with renal insufficiency develop secondary hyperparathyroidism (sHPT). Monotherapy with either active vitamin D or calcimimetics ameliorates sHPT. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley rats were subtotally nephrectomized (SNX), or sham-operated (sham-op) and subsequently randomized into the following treatment groups: SNX+R-568, SNX+calcitriol, SNX+vehicle, sham-op+R-568, sham-op+calcitriol, and sham-op+vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in-situ hybridization. PTH concentrations were lowered to the same extent by the two interventions, although phosphorus and Ca x P levels were reduced only by R-568 treatment. SNX rats developed marked albuminuria which was significantly reduced in fed ad libitum and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05±1.46 vs. 2.70±0.91 mm3) and podocyte volume (831±127 vs. 397±67 µm3), the degree of foot processes fusion (mean width of foot processes 958±364 vs. 272±35 nm) and GBM thickness (244±6 vs. 267±23 nm), as well as desmin staining were significantly higher in vehicle treated SNX compared with sham-op animals. These changes were ameliorated both with R-568 and calcitriol. In SNX as well as in sham-op animals, expression of the calcium sensing receptor (protein and mRNA) was upregulated by the treatment with the calcimimetic, but not with calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage.
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