Increased gene expression of components of the renin-angiotensin system in glomeruli of genetically hypertensive rats.
OBJECTIVE
The renin-angiotensin system (RAS) is implicated in the development of hypertensive glomerulosclerosis. However, no experimental evidence exists that clearly demonstrates activation of glomerular RAS in hypertensive nephropathy. We used stroke-prone spontaneously hypertensive rats (SHRSP) to examine whether RAS components are increased in glomeruli of SHRSP and whether this increase leads to an increase in mRNA levels for transforming growth factor-beta1 (TGF-beta1).


METHODS
We examined the sequential changes of urinary albumin excretion (UAE), morphology, and glomerular mRNA expression for TGF-beta1 and fibronectin (FN) in relation to glomerular mRNA expression for angiotensinogen (ATN), angiotensin converting enzyme (ACE), angiotensin II type 1a (AT1a), and type 1b (AT1b) receptors, and intervention with angiotensin II type 1 receptor antagonist candesartan and equihypotensive hydralazine.


RESULTS
In SHRSP, UAE was normal at 9 weeks of age, but became higher, beginning at 12 weeks of age, than that in the age-matched Wistar-Kyoto (WKY) rats, while SHRSP showed no glomerulosclerosis until 14 weeks of age; it was marked at 24 weeks. Plasma renin activity and plasma angiotensin II level was equivalent in the 9- and 12-week-old SHRSP and the WKY rats; both parameters, however, were elevated in 24-week-old SHRSP as compared with age-matched control. RNase protection assays showed that glomerular levels of ATN, ACE, and AT1a and AT1b receptors mRNA were significantly increased in 9-, 12-, and 14-week-old, but not in 24-week-old SHRSP, compared with age-matched WKY rats. Northern blot analysis showed that glomerular levels of TGF-beta1 and FN mRNA were higher in SHRSP than in WKY rats at all time points. Candesartan reduced UAE to control levels, whereas hydralazine reduced UAE but not to control levels. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis. While candesartan reduced mRNA levels for RAS components, TGF-beta1, and FN to control levels, hydralazine was not effective in this respect. Conclusion Results suggest that increases in glomerular RAS components that occur independently of circulating RAS alter glomerular permselectivity and increase the glomerular expression of TGF-beta1 and FN in young SHRSP. Findings in old SHRSP suggest that altered glomerular permselectivity and an increased glomerular expression of TGF-beta1 and FN may be associated with the activation of systemic RAS.
Obata
J
J
Department of Internal Medicine, Yamanashi Medical School, Japan.
Nakamura
T
T
Takano
H
H
Naito
A
A
Kimura
H
H
Yoshida
Y
Y
Shimizu
F
F
Guo
D F
DF
Inagami
T
T
D000419:Albuminuria / Q000235:genetics / Q000503:physiopathology; D000804:Angiotensin II / Q000097:blood; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure; D015152:Blotting, Northern; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000503:physiopathology; D006830:Hydralazine / Q000494:pharmacology; D006977:Hypertension, Renal / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000503:physiopathology*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; 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; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000235:genetics*; D012260:Ribonucleases; D013777:Tetrazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005353:Fibronectins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000808:Angiotensinogen; D000804:Angiotensin II; D006830:Hydralazine; D012260:Ribonucleases; D007703:Peptidyl-Dipeptidase A; D012083:Renin; C081643:candesartan