Renal expression of angiotensin receptors in long-term diabetes and the effects of angiotensin type 1 receptor blockade.
OBJECTIVE
The aims of this study were to assess the renal expression of angiotensin type 1 (AT1) and type 2 (AT2) receptors in diabetic spontaneously hypertensive rats (SHR) and the effect of AT1 receptor blockade on the expression of these receptors.


METHODS
Diabetes was induced by injection of streptozotocin in SHRs. Irbesartan, an AT1 receptor antagonist, was given to diabetic SHRs for 32 weeks (15 mg/kg per day, n = 10). Diabetic (n = 10) and non-diabetic SHRs (n = 10) were studied concurrently. A separate group of control and diabetic Wistar-Kyoto (WKY) rats were also evaluated.


METHODS
Gene and protein expressions of the AT1 and AT2 receptor were assessed by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry with specific antibodies andin vitro autoradiography with [125I]Sar(1), Ile(8) angiotensin II or [125I]CGP42112B.


RESULTS
Both AT1 and AT2 receptor mRNA levels in the kidney were reduced in diabetic SHRs compared to non-diabetic SHRs. Immunohistochemistry staining with specific antibodies showed a similar reduction in glomerular and tubulo-interstitial staining for both AT1 and AT2 receptors. Reduced binding for the AT1 and AT2 receptor was found in the kidney of diabetic SHRs. Diabetic SHRs developed albuminuria and had glomerular and tubulo-interstitial injury, which were prevented by treatment with irbesartan. Reduced expression of the AT1 receptor, but not the AT2 receptor, in diabetic SHRs was prevented by treatment with irbesartan. In diabetic WKY rats no such reduction in AT1 expression was observed, although there was a trend for reduced AT2 receptor expression.


CONCLUSIONS
These findings demonstrated that renal expression of both AT1 and AT2 receptor was reduced in long-term diabetic SHRs and that blockade of the AT1 receptor had disparate effects on expression of angiotensin II receptor subtypes.
Bonnet
Fabrice
F
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg West, Victoria 3081, Australia.
Candido
Riccardo
R
Carey
Robert M
RM
Casley
David
D
Russo
Leileata M
LM
Osicka
Tanya M
TM
Cooper
Mark E
ME
Cao
Zemin
Z
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D000077405:Irbesartan; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000077405:Irbesartan