Angiotensin II and IGF-I may interact to regulate tubulointerstitial cell kinetics and phenotypic changes in hypertensive rats.
Angiotensin II and insulin-like growth factor-I (IGF-I) are known to be actively involved in the pathogenesis of progressive renal injury, particularly in cell proliferation and phenotypic changes that contribute to tubulointerstitial injury. To investigate the possible mechanisms by which angiotensin II type 1 receptor antagonist (AIIA) ameliorates renal injury in a renal ablation model and to determine the contribution of phenotypic changes and IGF-I to morphological changes, we examined 1) whether AIIA attenuated phenotypic changes as markers of alpha-smooth muscle actin (SMA) and vimentin, 2) whether AIIA altered renal IGF-I expression, and 3) the changes of tubulointerstitial cell kinetics between apoptosis (tested via terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling, TUNEL) and cell proliferation (a test of proliferating cell nuclear antigen, PCNA). Following a sham operation (sham) or 5/6 nephrectomy (Nx), we administered E4177, a potent, selective competitive angiotensin II type 1 receptor antagonist (AIIA), for 10 weeks. In Nx rats, SMA and vimentin expressions developed in injured tubulointerstitium, particularly in hypoperfused scar-adjacent areas, and there was an increase in renal IGF-I expressions. The TUNEL score increased 5-fold and PCNA increased 8-fold, compared with TUNEL and PCNA measurements in sham-operated rats. Renin expression in the juxtaglomerular apparatus was markedly suppressed in the Nx group, although de novo tubular renin expression appeared in Nx, compared with that in the sham group. E4177, both 10 mg/kg (AIIA 10) and 1 mg/kg (AIIA 1), markedly ameliorated renal injury, although blood pressure was less affected in AIIA 1. Both AIIA 10 and AIIA 1 suppressed the neoexpressions of SMA and vimentin in an association with decreased IGF-I expression. Regarding cell kinetics, neither AIIA 10 nor AIIA 1 decreased the TUNEL score; rather, tended to increase, while PCNA was significantly suppressed by AIIA. In conclusion, one of the underlying protective mechanisms of AIIA in this model may be related to the modulations of angiotensin II-induced phenotypic changes and tubulointerstitial cell kinetics through IGF-I.
Kobayashi
Shuzo
S
Kidney & Dialysis Center, Shonan Kamakura General Hospital, Japan. shuzo@shonankamakura.co.jp
Moriya
Hidekazu
H
Nakabayashi
Iwao
I
Nishiyama
Jyunichiro
J
Fukuda
Taneo
T
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D012083:Renin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D000199:Actins; D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D014746:Vimentin; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D012083:Renin