A novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in rat vascular smooth muscle and renal proximal tubular cells.
Angiotensin II stimulates cellular hypertrophy in cultured vascular smooth muscle and renal proximal tubular cells. This effect is believed to be one of earliest morphological changes of heart and renal failure. However, the precise molecular mechanism involved in angiotensin II-induced hypertrophy is poorly understood. In the present study we report the isolation of a novel angiotensin II type 1 receptor-associated protein. It encodes a 531-amino acid protein. Its mRNA is detected in all human tissues examined but highly expressed in the human kidney, pancreas, heart, and human embryonic kidney cells as well as rat vascular smooth muscle and renal proximal tubular cells. Protein synthesis and relative cell size analyzed by flow cytometry studies indicate that overexpression of the novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in cultured rat vascular smooth muscle and renal proximal tubular cells. In contrast, the hypertrophic effects was reversed in renal proximal tubular cell lines expressing the novel gene in the antisense orientation and its dominant negative mutant, which lacks the last 101 amino acids in its carboxyl-terminal tail. The hypertrophic effects are at least in part mediated via protein kinase B activation or cyclin-dependent kinase inhibitor, p27(kip1) protein expression level in vascular smooth muscle, and renal proximal tubular cells. Moreover, angiotensin II could not stimulate cellular hypertrophy in renal proximal tubular cells expressing the novel gene in the antisense orientation and its mutant. These findings may provide new molecular mechanisms to understand hypertrophic agents such as angiotensin II-induced cellular hypertrophy.
Guo
Deng-Fu
DF
Department of Medicine, University of Montreal and Research Center, CHUM-Hotel-Dieu Hospital, 3850 St.-Urbain, Montreal, Quebec H2W 1T8, Canada. guod@magellan.umontreal.ca
Tardif
Valerie
V
Ghelima
Karin
K
Chan
John S D
JS
Ingelfinger
Julie R
JR
Chen
XiangMei
X
Chenier
Isabelle
I
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D016384:Consensus Sequence; D017931:DNA Primers; D006801:Humans; D006984:Hypertrophy; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000502:physiology*; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D011945:Receptors, Angiotensin / Q000235:genetics / Q000502:physiology*; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
C449676:AGTRAP protein, human; D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin