Candesartan augments compensatory changes in medullary transport proteins in the diabetic rat kidney.
Volume depletion due to persistent glucosuria-induced osmotic diuresis is a significant problem in uncontrolled diabetes mellitus (DM). Angiotensin II receptor blockers (ARBs), such as candesartan, slow the progression of chronic kidney disease in patients with DM. However, mice with genetic knockout of components of the renin-angiotensin system have urine concentrating defects, suggesting that ARBs may exacerbate the volume depletion. Therefore, the effect of candesartan on UT-A1, UT-A3, NKCC2, and aquaporin-2 (AQP2) protein abundances was determined in control and 3-wk DM rats. Aldosterone levels in control rats (0.36 +/- 0.06 nM) and candesartan-treated rats (0.34 +/- 0.14 nM) were the same. DM rats had higher aldosterone levels (1.48 +/- 0.37 nM) that were decreased by candesartan (0.97 +/- 0.26 nM). Western analysis showed that UT-A1 expression was increased in DM rats compared with controls in inner medullary (IM) tip (158 +/- 13%) and base (120 +/- 25%). UT-A3 abundance was increased in IM tip (123 +/- 11%) and base (146 +/- 17%) of DM rats vs. controls. UT-A3 was unchanged in candesartan-treated control rats. In candesartan-treated DM rats, UT-A3 increased in IM tip (160 +/- 14%) and base (210 +/- 19%). Candesartan-treated DM rats had slightly higher AQP2 in IM (46%, P < 0.05) vs. control rats. NKCC2/BSC1 was increased 145 +/- 10% in outer medulla of DM vs. control rats. We conclude that candesartan augments compensatory changes in medullary transport proteins, reducing the losses of solute and water during uncontrolled DM. These changes may represent a previously unrecognized beneficial effect of type 1 ARBs in DM.
Blount
Mitsi A
MA
Emory Univ. School of Medicine, Renal Division, 1639 Pierce Drive, NE, WMB Rm. 3319B, Atlanta, GA 30322, USA.
Sands
Jeff M
JM
Kent
Kimilia J
KJ
Smith
Tekla D
TD
Price
S Russ
SR
Klein
Janet D
JD
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism*; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D007671:Kidney Concentrating Ability / Q000187:drug effects; D007679:Kidney Medulla / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D013777:Tetrazoles / Q000494:pharmacology*; D014882:Water-Electrolyte Balance / Q000187:drug effects; D000096982:Urea Transporters
D047228:Angiotensin II Type 1 Receptor Blockers; D051399:Aquaporin 2; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D026901:Membrane Transport Proteins; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D013777:Tetrazoles; D000096982:Urea Transporters; C496025:Aqp2 protein, rat; C578715:Slc12a1 protein, mouse; C578716:Slc12a1 protein, rat; C081643:candesartan