title: Unilateral ureteral obstruction attenuates intrarenal angiotensin II generation induced by podocyte injury.
abstract: The renal tissue renin-angiotensin system is activated in chronic kidney diseases. We previously demonstrated that intrarenal ANG II is synthesized primarily from liver-derived angiotensinogen filtered through the glomerulus and that podocyte injury increases the passage of angiotensinogen into the tubular lumen and generation of ANG II. In the present study, we tested the effect of cessation of glomerular filtration by ureteral obstruction on renal ANG II generation in kidneys with podocyte injury under two experimental conditions. Ureteral obstruction is known to activate the renin-angiotensin system in nonproteinuric kidneys. Transgenic mice expressing hCD25 in podocyte (NEP25) were injected with 1.25 or 10 ng/g body wt of LMB2, a hCD25-targeted immunotoxin, subjected to unilateral ureteral ligation on the following day, and euthanized 7 and 4 days later, respectively. In both experiments, compared with the kidney in untreated wild-type mice, renal angiotensinogen protein, as assessed by immunostaining and Western blot analysis, was increased in the contralateral unobstructed kidney. However, it was markedly decreased in the obstructed kidney. Whereas intrarenal ANG II content was increased in the contralateral kidney compared with the untreated kidney (248 ± 83 vs. 106 ± 21 and 298 ± 185 vs. 64.8 ± 20 fmol/g kidney, respectively), this increase was suppressed in the obstructed kidney (161 ± 75 and 113 ± 34 fmol/g kidney, respectively), a pattern opposite to what we expected in obstructed kidneys without podocyte injury. Thus, our study indicates that the major source of increased renal ANG II in podocyte injury is filtered angiotensinogen.
authors: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan;
authors: Masahiro
authors: M
authors: Okabe
authors: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan;
authors: Yoichi
authors: Y
authors: Miyazaki
authors: Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan; and.
authors: Fumio
authors: F
authors: Niimura
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland;
authors: Ira
authors: I
authors: Pastan
authors: Department of Pharmacology, Kagawa University School of Medicine, Kagawa, Japan;
authors: Akira
authors: A
authors: Nishiyama
authors: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan;
authors: Takashi
authors: T
authors: Yokoo
authors: Tokai University School of Medicine, Kanagawa, Japan; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Iekuni
authors: I
authors: Ichikawa
authors: Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan; Institute of Medical Science, taijim@is.icc.u-tokai.ac.jp.
authors: Taiji
authors: T
authors: Matsusaka
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000804:Angiotensin II / Q000378:metabolism*; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal; D004195:Disease Models, Animal; D015536:Down-Regulation; D005098:Exotoxins; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000911:Antibodies, Monoclonal; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D005098:Exotoxins; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D000808:Angiotensinogen; D000804:Angiotensin II
keywords: glomerulosclerosis; intrarenal angiotensin II; renin-angiotensin system; unilateral ureteral obstruction