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Articles in PresS, published online ahead of print August 8, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.0101.2001
Submitted on March 23, 2001
Accepted on July 12, 2001
1 The Water and Salt Research Center, Univ. of Aarhus, Aarhus, Denmark
2 The Water and Salt Research Center, Univ. of Aarhus, Aarhus, Denmark; Dept. of Physiology, Dongguk Univ., Kyungju, Korea, Republic of
3 Lab. of Kidney and Electrolyte Metabolism, National heart, Lung, and Blood Institute, National Inst. of Health, Bethesda, Maryland, USA
* To whom correspondence should be addressed. E-mail: sn{at}ana.au.dk.
Chronic hypercalcemia (HC) is accompanied by urinary concentration defects and functional studies indicate defects in the loop of Henle. However, the molecular basis for the urinary concentration defect in HC remains undefined. We hypothesize that dysregulation of renal sodium transporters may play an important role in this. DHT-induced hypercalcemia produced significant polyuria, reduced urinary concentration, as well as increased urinary sodium and phosphate excretion in rats. Semiquantitative immunoblotting revealed a marked reduction in the abundance of the thick ascending limb (TAL) BSC-1 in membrane fractions from the inner stripe of the outer medulla (ISOM; 36 ± 5%) and whole kidney (51 ± 11%) in HC compared with controls. Consistent with this finding, immunocytochemistry and immunoelectron microscopy demonstrated that BSC-1 immunolabeling in the apical plasma membrane and subapical intracellular vesicles of thick ascending limb cells was markedly reduced in rats with HC. Immunoblotting and immunohistoochemical labeling of the potassium channel Kir 1.1 (ROMK; serves K+ recycling in the TAL) was also reduced in hypercalcemic rats. In contrast there were no reductions in the expression of NHE3 and Na,K-ATPase in ISOM. The abundance of the proximal tubule NaPi-2 was significantly reduced (25 ± 4% of control levels), consistent with a dramatic increase in urinary phosphate excretion. Na-K-ATPase and NHE3 abundance were not altered in kidney cortex/outer stripe of the outer medulla, and there was no change in the subcellular localization of NHE3 in proximal tubule and TAL. In conclusion 1) The markedly decreased apical plasma membrane expression levels and protein abundance of the Na-K-2Cl cotransporter BSC-1 and ROMK in TAL is likely to play a major role in the urinary concentration defects associated with hypercalcemia; 2) the reduced abundance of the NaPi-2 in the proximal tubule is likely to play a role in the increased urinary phosphate excretion.
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