Regulation of angiotensin type 1 receptor and its gene expression: role in renal growth.
Low sodium intake has been demonstrated to upregulate the gene expression of the predominant renal type 1 angiotensin II (Ang II) receptor (AT1), the AT1A subtype. The study presented here tests the hypothesis that the upregulation of renal AT1 mRNA induced by sodium depletion occurs conjointly with an elevation of the AT1 receptor that modulates renal growth. Seven-week-old male Wistar rats were divided into four groups and treated for 2 wk with normal sodium diet, normal sodium diet plus 3 mg/kg/day losartan, low sodium diet, or low sodium diet plus losartan. Body weight and MAP were not significantly different among the four groups. Plasma renin activity was significantly elevated by losartan treatment, low salt intake, or a combination of the two, compared with the plasma renin activity of the controls. Northern blot analysis indicated that renal AT1 mRNA levels were significantly increased-183% by losartan, 212% by low salt intake, and 227% by the combination of the two-compared with their levels in controls. Radioligand binding assays revealed that AT1 receptors were significantly increased by low salt intake but were significantly decreased by losartan treatment. Renal AT1 receptor binding in the rats subjected to sodium depletion plus losartan did not differ from that in control rats. Kidney weight, kidney weight/body weight ratio, and renal DNA and protein content were not altered by sodium depletion but were significantly lowered by losartan treatment with both normal and low sodium intake, compared with those of controls. The protein/DNA ratio was not significantly different among the four groups. Blockade of renal AT1 receptors with losartan was found to retard normal renal growth, indicating that Ang II is required for normal renal development. Low sodium intake was found to increase mRNA and expression of the renal AT1 receptor but to have no effect on renal growth, suggesting that an increase in renal mass above a normal level requires the activation of multiple factors. Blockade of the AT1 receptor by losartan was found to upregulate AT1 mRNA but to down-regulate the AT1 receptor, suggesting that AT1 receptor-mediated intracellular events are necessary to sustain functional AT1 receptor expression in the kidney.
Wang
D H
DH
Department of Internal Medicine, University of Texas Medical Branch, Galveston 77555-1065, USA.
Du
Y
Y
Zhao
H
H
Granger
J P
JP
Speth
R C
RC
Dipette
D J
DJ
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D004039:Diet, Sodium-Restricted; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D019808:Losartan; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology
D001713:Biphenyl Compounds; D007093:Imidazoles; D012333:RNA, Messenger; D013777:Tetrazoles; D012083:Renin; D019808:Losartan