Comparison of ROCK and EGFR activation pathways in the progression of glomerular injuries in AngII-infused rats.
OBJECTIVE
The roles of rho-kinase (ROCK) and epidermal growth factor receptor (EGFR) were studied using an angiotensin II (AngII)-dependent hypertension rat model.


METHODS
Male Wistar rats were infused with AngII at a rate of 400 ng/kg body weight (BW)/min for 14 days. Effects of ROCK inhibitor, fasudil (20 mg/kg BW), and EGFR inhibitor, gefitinib (3 mg/kg BW), were studied.


RESULTS
AngII infusion increased blood pressure (BP; 220 ± 19 mmHg) as well as the number of proliferating cells in glomeruli judged by Ki67 and proliferating cell nuclear antigen immunostaining and urinary protein excretion (118 ± 19 mg/day). AngII also decreased p27 expression and increased cyclin D1 expression in glomeruli, as well as induced dissociation of the nephrin- and podocin-immunostaining patterns in podocytes. Treatment with fasudil or gefitinib completely inhibited glomerular cell proliferation without changing the BP. Although the decreased p27 expression was reversed by both treatments, cyclin D1 induction was abolished only by gefitinib. Fasudil significantly reduced proteinuria (57.2 ± 17.5 mg/day), but not gefitinib (133.3 ± 30.9 mg/day). The dissociation of podocin and nephrin was ameliorated by fasudil, but not by gefitinib.


CONCLUSIONS
ROCK and EGFR have distinct roles in proteinuria and glomerular cell proliferation in this model.
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan. phillies4331@nifty.com
Hiroyuki
H
Suzuki
Tatsuo
T
Yamamoto
Yoshihide
Y
Fujigaki
Satoru
S
Eguchi
Akira
A
Hishida
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D000077156:Gefitinib; D007674:Kidney Diseases / Q000209:etiology*; D007678:Kidney Glomerulus; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000804:Angiotensin II; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D066246:ErbB Receptors; D054460:rho-Associated Kinases; C049347:fasudil; D000077156:Gefitinib