Complement 3 activates the renal renin-angiotensin system by induction of epithelial-to-mesenchymal transition of the nephrotubulus in mice.
We have demonstrated that mesenchymal cells from spontaneously hypertensive rats genetically express complement 3 (C3). Mature tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT) that is linked to the pathogenesis of renal fibrosis and injury. In this study, we investigated the contribution of C3 in EMT and in the renal renin-angiotensin (RA) systems associated with hypertension. C3a induced EMT in mouse TCMK-1 epithelial cells, which displayed increased expression of renin and Krüppel-like factor 5 (KLF5) and nuclear localization of liver X receptor α (LXRα). C3 and renin were strongly stained in the degenerated nephrotubulus and colocalized with LXRα and prorenin receptor in unilateral ureteral obstruction (UUO) kidneys from wild-type mice. In C3-deficient mice, hydronephrus and EMT were suppressed, with no expression of renin and C3. After UUO, systolic blood pressure was increased in wild-type but not C3-deficient mice. In wild-type mice, intrarenal angiotensin II (ANG II) levels were markedly higher in UUO kidneys than normal kidneys and decreased with aliskiren. There were no increases in intrarenal ANG II levels after UUO in C3-deficient mice. Thus C3 induces EMT and dedifferentiation of epithelial cells, which produce renin through induction of LXRα. These data indicate for the first time that C3 may be a primary factor to activate the renal RA systems to induce hypertension.
Div. of Nephrology, Hypertension, and Endocrinology, Dept. of Medicine, Nihon Univ. School of Medicine, Tokyo 173-8610, Japan. fukuda.noboru@nihon-u.ac.jp.
Xueli
X
Zhou
Noboru
N
Fukuda
Hiroyuki
H
Matsuda
Morito
M
Endo
Xiaofei
X
Wang
Kosuke
K
Saito
Takahiro
T
Ueno
Taro
T
Matsumoto
Koichi
K
Matsumoto
Masayoshi
M
Soma
Naohiko
N
Kobayashi
Akira
A
Nishiyama
D000450:Aldosterone / Q000097:blood; D000577:Amides; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents; D003176:Complement C3 / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005650:Fumarates; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009400:Nephrosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction; D000092502:Renin Inhibitors
D000450:Aldosterone; D000577:Amides; D000804:Angiotensin II; D000959:Antihypertensive Agents; D003176:Complement C3; D005650:Fumarates; D051741:Kruppel-Like Transcription Factors; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012083:Renin; D053773:Transforming Growth Factor beta1; D000092502:Renin Inhibitors; C118391:Klf5 protein, mouse; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; C508961:Tgfb1 protein, mouse; C446481:aliskiren
angiotensin II; complement 3; epithelial-to-mesenchymal transition; nephrotubulus; renin