Identification of bona fide alternative renin transcripts expressed along cortical tubules and potential roles in promoting insulin resistance in vivo without significant plasma renin activity elevation.
Renin belongs to a family of aspartyl proteases and is the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II. Processing of renal renin has been extensively investigated in juxtaglomerular granular cells, in which prorenin and active renin are present in secretory condensed granules. Previous studies demonstrated alternative renin transcription in rat adrenal glands. Different studies reported novel intracellular forms of renin deduced from novel 5' variants derived from renin mRNA in both mice and humans. Comprehensive detailed studies in genetically engineered mice showed that both a secreted and an intracellular form of renin plays divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system; however, the presence, regulation, and functions of these renin isoforms in kidney and adrenal gland are not fully understood in mice. To investigate the characteristics of renin isoforms in mice, we performed a systematic inventory of renin transcripts of mice with and without a duplication of the renin gene alternatively from previous studies. We discovered a novel isoform of renin of the Ren2 gene, which conserved functionally important residues of the prosegment and incomplete isoforms of the Ren1C/D gene lacking a pre-pro segment. In situ hybridization assays revealed alternative renin isoforms expressed along cortical tubules. Newly generated transgenic mice with systemic overexpression of alternative renin transcript showed enhanced local angiotensin II generation without elevation of plasma renin activity and systemic insulin resistance in vivo, providing new pathophysiological insights into insulin resistance exaggerated by bona fide renin isoform.
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan. tommmish@hotmail.com.
Tomoaki
T
Ishigami
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Tabito
T
Kino
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Lin
L
Chen
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Shintaro
S
Minegishi
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Naomi
N
Araki
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Masanari
M
Umemura
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Kaito
K
Abe
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Rie
R
Sasaki
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Hisako
H
Yamana
From the Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Satoshi
S
Umemura
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D007333:Insulin Resistance / Q000235:genetics*; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D012083:Renin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology
D012083:Renin
alternative transcript; insulin resistance; renin