Angiotensin II formation in the kidney and nephrosclerosis in Ren-2 hypertensive rats.
BACKGROUND
Ren-2 transgenic hypertensive rats develop malignant hypertensive nephrosclerosis despite low to normal plasma angiotensin II and suppressed renal renin. We tested the hypothesis that local angiotensin II formation occurs at sites of renal vascular and interstitial injury in this model.


METHODS
Heterozygous Ren-2 transgenic rats were compared with normotensive Sprague-Dawley-Hannover control rats and Ren-2 transgenic rats treated with a very low dose of an angiotensin II type 1 (AT1) receptor antagonist, 1 mg/kg/day losartan, for 4 weeks. Blood pressure measurements, quantifications of urinary albumin, plasma and tissue angiotensin II as well as immunohistochemical analyses were performed.


RESULTS
Systolic blood pressure was not affected by losartan during the study but intra-arterial recordings revealed a decrease of blood pressure. Losartan reduced albumin excretion, cell proliferation, macrophage influx, collagen I and collagen IV deposition. Plasma angiotensin II was decreased, while kidney tissue angiotensin II content was increased in Ren-2 transgenic rats compared with control rats. In Ren-2 transgenic rats, juxtaglomerular renin and angiotensin II staining were reduced, but there was a marked angiotensin II staining at foci of tubulo-interstitial fibrosis and at proliferative malignant vascular lesions.


CONCLUSIONS
We conclude that local angiotensin II formation is increased in proliferative or fibrotic kidney lesions in the Ren-2 transgenic rat. Local angiotensin II formation may help to explain why the AT1 receptor antagonist prevents or ameliorates this transgenic model of malignant nephrosclerosis despite low to normal plasma angiotensin II and suppressed renal renin.
Hartner
Andrea
A
University Hospital for Children and Adolescents, University of Erlangen-Nuremberg, Erlangen, Germany. andrea.hartner@rzmail.uni-erlangen.de
Porst
Markus
M
Klanke
Bernd
B
Cordasic
Nada
N
Veelken
Roland
R
Hilgers
Karl F
KF
D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D049109:Cell Proliferation; D006579:Heterozygote; D006973:Hypertension; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D009400:Nephrosclerosis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics
C473112:Ren2 protein, mouse; D000804:Angiotensin II; D012083:Renin