title: Podocyte injury enhances filtration of liver-derived angiotensinogen and renal angiotensin II generation.
abstract: Intrarenal angiotensin II is increased in kidney diseases independently of plasma angiotensin II and is thought to promote progressive deterioration of renal architecture. Here we investigated the mechanism of enhanced renal angiotensin II generation in kidney glomerular diseases. For this, kidney- or liver-specific angiotensinogen gene (Agt) knockout was superimposed on the mouse model of inducible podocyte injury (NEP25). Seven days after induction of podocyte injury, renal angiotensin II was increased ninefold in NEP25 mice with intact Agt, accompanied by increases in urinary albumin and angiotensinogen excretion, renal angiotensinogen protein, and its mRNA. Kidney Agt knockout attenuated renal Agt mRNA but not renal angiotensin II, renal, or urinary angiotensinogen protein. In contrast, liver Agt knockout markedly reduced renal angiotensin II to 18.7% of that of control NEP25 mice, renal and urinary angiotensinogen protein, but not renal Agt mRNA. Renal angiotensin II had no relationship with renal Agt mRNA, or with renal renin mRNA, which was elevated in liver Agt knockouts. Kidney and liver dual Agt knockout mice showed phenotypes comparable to those of liver Agt knockout mice. Thus, increased renal angiotensin II generation upon severe podocyte injury is attributed to increased filtered angiotensinogen of liver origin resulting from loss of macromolecular barrier function of the glomerular capillary wall that occurs upon severe podocyte injury.
authors.affiliation: 1] Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan [2] Institute of Medical Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Niimura
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: 1] Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA [2] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Shintani
authors.affiliation: Department of Pharmacology, Research Equipment Center, and Second Department of Internal Medicine, Kagawa University School of Medicine, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA [2] Tokai University School of Medicine, Isehara, Japan [3] Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Iekuni
authors.initials: I
authors.lastname: Ichikawa
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000804:Angiotensin II / Q000378:metabolism*; D000808:Angiotensinogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D000818:Animals; D000911:Antibodies, Monoclonal; D004195:Disease Models, Animal; D005098:Exotoxins; D005838:Genotype; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C534932:Agt protein, mouse; D000911:Antibodies, Monoclonal; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D005098:Exotoxins; D008565:Membrane Proteins; D012333:RNA, Messenger; C113267:nephrin; D000808:Angiotensinogen; D000804:Angiotensin II; D012964:Sodium