Altered expression of renal aquaporins and Na(+) transporters in rats treated with L-type calcium blocker.
Nifedipine, a calcium antagonist, has diuretic and natriuretic properties. However, the molecular mechanisms by which these effects are produced are poorly understood. We examined kidney abundance of aquaporins (AQP1, AQP2, and AQP3) and major sodium transporters [type 3 Na/H exchanger (NHE-3); type 2 Na-Pi cotransporter (NaPi-2); Na-K-ATPase; type 1 bumetanide-sensitive cotransporter (BSC-1); and thiazide-sensitive Na-Cl cotransporter (TSC)] as well as inner medullary abundance of AQP2, phosphorylated-AQP2 (p-AQP2), AQP3, and calcium-sensing receptor (CaR). Rats treated with nifedipine orally (700 mg/kg) for 19 days had a significant increase in urine output, whereas urinary osmolality and solute-free water reabsorption were markedly reduced. Consistent with this, immunoblotting revealed a significant decrease in the abundance of whole kidney AQP2 (47 +/- 7% of control rats, P < 0.05) and in inner medullary AQP2 (60 +/- 7%) as well as in p-AQP2 abundance (17 +/- 6%) in nifedipine-treated rats. In contrast, whole kidney AQP3 abundance was significantly increased (219 +/- 28%). Of potential importance in modulating AQP2 levels, the abundance of CaR in the inner medulla was significantly increased (295 +/- 25%) in nifedipine-treated rats. Nifedipine treatment was also associated with increased urinary sodium excretion. Consistent with this, semiquantitative immunoblotting revealed significant reductions in the abundance of proximal tubule Na(+) transporters: NHE-3 (3 +/- 1%), NaPi-2 (53 +/- 12%), and Na-K-ATPase (74 +/- 5%). In contrast, the abundance of the distal tubule Na-Cl cotransporter (TSC) was markedly increased (240 +/- 29%), whereas BSC-1 in the thick ascending limb was not altered. In conclusion, 1) increased urine output and reduced urinary concentration in nifedipine-treated-rats may, in part, be due to downregulation of AQP2 and p-AQP2 levels; 2) CaR might be involved in the regulation of water reabsorption in the inner medulla collecting duct; 3) reduced expression of proximal tubule Na(+) transporters (NHE-3, NaPi-2, and Na, K-ATPase) may be involved in the increased urinary sodium excretion; and 4) increase in TSC expression may occur as a compensatory mechanism.
Wang
W
W
Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus, Denmark.
Kwon
T H
TH
Li
C
C
Flyvbjerg
A
A
Knepper
M A
MA
Frøkiaer
J
J
Nielsen
S
S
D000818:Animals; D020346:Aquaporins / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004231:Diuresis / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology*; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters; D014556:Urine / Q000737:chemistry
D020346:Aquaporins; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters; C473605:extracellular calcium cation-sensing receptor, rat; D012964:Sodium; D009543:Nifedipine