Renal protective effect of TCV-116 in stroke-prone spontaneously hypertensive rats.
We examined the effects of TCV-116, a non-peptide selective AT1 receptor antagonist, on cellular phenotype and on the expression of the transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix genes in the kidneys of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given vehicle or TCV-116 (10 mg/kg/day) by gastric gavage for 10 weeks (from the age of 22 to 32 weeks). Renal mRNA levels were measured by Northern blot analysis. In vehicle-treated 32-week-old SHRSP, urinary albumin excretion per 24 h was about 26-fold greater than that in age-matched Wistar-Kyoto (WKY) rats, and the mRNA levels of renal TGF-beta 1, fibronectin and collagen types I and III in SHRSP were all several-fold higher than those in WKY. Immunohistochemical studies showed the prominent presence of alpha-smooth muscle actin-expressing glomerular cells in SHRSP, in contrast to their absence in WKY. Treatment of SHRSP with TCV-116 decreased urinary albumin excretion and renal mRNA levels for TGF-beta 1 and for the above-mentioned extracellular matrix components. TCV-116 prevented the phenotypic modulation of glomerular cells in SHRSP. These results suggest that AT1 receptor antagonists may have powerful renal protective effects.
Kim
S
S
Department of Pharmacology, Osaka City University Medical School, Japan.
Ohta
K
K
Hamaguchi
A
A
Omura
T
T
Yukimura
T
T
Miura
K
K
Inada
Y
Y
Wada
T
T
Ishimura
Y
Y
Chatani
F
F
D000419:Albuminuria / Q000652:urine; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D002561:Cerebrovascular Disorders / Q000503:physiopathology; D005109:Extracellular Matrix / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006977:Hypertension, Renal / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000502:physiology; D008297:Male; D010641:Phenotype; D011355:Prodrugs / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011945:Receptors, Angiotensin / Q000502:physiology; D012598:Sclerosis; D013777:Tetrazoles; D016212:Transforming Growth Factor beta / Q000235:genetics
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C077793:candesartan cilexetil