Renoprotective effects of carvedilol in hypertensive-stroke prone rats may involve inhibition of TGF beta expression.
1. The effect of carvedilol on renal function, structure and expression of TGF beta and the matrix proteins fibronectin, collagen I and collagen III, was evaluated in spontaneously hypertensive stroke-prone (SHR-SP) rats fed a high fat, high salt diet. 2. Carvedilol treatment for 11 to 18 weeks did not alter systolic blood pressure in SHR-SP rats, however, it resulted in a significant reduction in heart rate. 3. Carvedilol treatment reduced renal fibrosis and total, active and chronic renal damage to levels approaching those of WKY rats on a normal diet. 4. Urinary protein excretion was higher in SHR-SP rats (51+/-10 mg day(-1)) than WKY rats (18+/-2 mg day(-1)) and this was further increased when SHR-SP rats were fed a high fat, high salt diet (251+/-120 mg day(-1)). Treatment with carvedilol resulted in significantly lower urinary protein excretion (37+/-15 mg day(-1)). 5. The expression of TGF beta mRNA was significantly higher in SHR-SP rats compared to WKY rats and a further increase was observed when rats were fed a high fat, high salt diet. Renal TGF beta expression was significantly reduced by treatment with carvedilol. The expression of fibronectin and collagen I and collagen III mRNA showed a pattern similar to that observed with TGF beta mRNA expression. Collagen I mRNA expression followed a pattern similar to renal fibrosis. 6. These data indicate that carvedilol can provide significant renal protection in the absence of any antihypertensive activity and that the mechanisms involved in this action may include reduced expression of profibrotic factors such as TGF beta.
Wong
V Y
VY
Department of Renal Pharmacology, GlaxoSmithKline, King of Prussia, Pennsylvania, PA 19406, USA.
Laping
N J
NJ
Nelson
A H
AH
Contino
L C
LC
Olson
B A
BA
Gygielko
E
E
Campbell
W G
WG
Barone
F
F
Brooks
D P
DP
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D024042:Collagen Type I / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D005353:Fibronectins / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011412:Propanolamines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012720:Severity of Illness Index; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D016212:Transforming Growth Factor beta / Q000235:genetics*
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D024042:Collagen Type I; D004041:Dietary Fats; D005353:Fibronectins; D011412:Propanolamines; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D016212:Transforming Growth Factor beta; D000077261:Carvedilol