Local renal aldosterone system and its regulation by salt, diabetes, and angiotensin II type 1 receptor.
CYP11B2 is the enzyme responsible for aldosterone synthesis mainly in the adrenal gland. In this study, we hypothesized that CYP11B2 gene, protein, and aldosterone are produced locally in kidney and regulated by low salt intake, angiotensin II type 1 (AT1) receptor and insulin-deficient diabetes hyperglycemia. We used real-time RT-PCR, immunohistochemistry staining, and microdialysis techniques to monitor changes in renal CYP11B2 mRNA and protein and aldosterone production in normal, adrenalectomized, or streptozotocin-induced insulin-deficient diabetic hyperglycemic rats. In normal kidney, CYP11B2 mRNA and protein were localized mainly in the renal cortex and upregulated by angiotensin II and low salt intake. The angiotensin II effect was reversed by AT1 receptor blocker valsartan. Immunohistochemistry staining demonstrated presence of CYP11B2 in glomeruli. Although aldosterone was absent in plasma of adrenalectomized rats, it was present in renal interstitium and tissue. Diabetes increased renal cortical and total kidney CYP11B2 mRNA and protein. Lowering blood glucose with insulin decreased total renal CYP11B2 mRNA and protein. Despite lack of significant changes in blood glucose, valsartan treatment caused significant reduction in renal CYP11B2 mRNA and protein. In presence of diabetes, there was an increase in CYP11B2 immunostaining in glomeruli and proximal tubules. This expression was abrogated with insulin or valsartan treatment. These results demonstrate the presence of all components of local renal aldosterone system. This system is physiologically active because it is regulated by angiotensin II and low salt intake. In insulin-deficient diabetes hyperglycemia rat model, glucose, insulin, and AT1 receptor modulate CYP11B2 expression in the kidney.
Xue
Chun
C
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia, USA.
Siragy
Helmy M
HM
D000315:Adrenalectomy; D000450:Aldosterone / Q000096:biosynthesis / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D019405:Cytochrome P-450 CYP11B2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012965:Sodium Chloride / Q000008:administration & dosage* / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014018:Tissue Distribution; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D007328:Insulin; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D012965:Sodium Chloride; D000450:Aldosterone; D000068756:Valsartan; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C120361:Cyp11b3 protein, rat; D019405:Cytochrome P-450 CYP11B2; D014633:Valine