Angiotensin II type 1 receptor blockade ameliorates tubulointerstitial injury induced by chronic potassium deficiency.
BACKGROUND
Chronic potassium (K+) deficiency, one of the well-known causes of renal tubulointerstitial injury, is associated with an alteration in vasoactive mediators including persistent generation of renal cortical angiotensin (Ang) II despite the suppression of plasma Ang II, and suppression of urinary nitrite/nitrate excretion. We tested the hypothesis that K+-deficiency-induced renal tubulointerstitial injury could be mediated by Ang II or a reduction in nitric oxide.


METHODS
Rats were fed a K+-deficient diet (0.01% K+) alone, or with either losartan or l-arginine (L-Arg) in drinking water. Control rats were fed with a normal K+ diet (0.36% K+). At the end of 10 weeks, kidneys were excised and renal injury was evaluated.


RESULTS
Serum K+ was similarly depressed in all three groups receiving the K+-deficient diet. Rats on the K+-deficient diet alone developed renal hypertrophy and tubulointerstitial fibrosis with an increase in tubular osteopontin expression, macrophage infiltration and type III collagen deposition. Administration of losartan significantly reduced renal hypertrophy and prevented tubulointerstitial injury in the cortex, although some medullary injury occurred. In contrast, administration of L-Arg did not attenuate tubulointerstitial injury in the cortex, despite a complete recovery of urinary nitrate excretion. Mild but significant improvement of tubular osteopontin expression and macrophage infiltration were observed in the medulla of L-Arg-treated hypokalemic rats.


CONCLUSIONS
These results indicate that hypokalemic renal injury is mediated, at least in part, by Ang II via the Ang II type 1 receptor, with a lesser contribution mediated by a reduction in nitric oxide. Losartan may be beneficial in preventing hypokalemic tubulointerstitial injury.
Suga
Shin-Ichi
S
Division of Nephrology, University of Washington Medical Center, Seattle, Washington, USA.
Mazzali
Marilda
M
Ray
Patricio E
PE
Kang
Duk-Hee
DH
Johnson
Richard J
RJ
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002908:Chronic Disease; D015232:Dinoprostone / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009566:Nitrates / Q000652:urine; D009573:Nitrites / Q000652:urine; D011191:Potassium Deficiency / Q000473:pathology* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1
D057911:Angiotensin Receptor Antagonists; D009566:Nitrates; D009573:Nitrites; D044140:Receptor, Angiotensin, Type 1; D001120:Arginine; D019808:Losartan; D015232:Dinoprostone