title: Liver angiotensinogen is the primary source of renal angiotensin II.
abstract: Angiotensin II content in the kidney is much higher than in the plasma, and it increases more in kidney diseases through an uncertain mechanism. Because the kidney abundantly expresses angiotensinogen mRNA, transcriptional dysregulation of angiotensinogen within the kidney is one potential cause of increased renal angiotensin II in the setting of disease. Here, we observed that kidney-specific angiotensinogen knockout mice had levels of renal angiotensinogen protein and angiotensin II that were similar to those levels of control mice. In contrast, liver-specific knockout of angiotensinogen nearly abolished plasma and renal angiotensinogen protein and renal tissue angiotensin II. Immunohistochemical analysis in mosaic proximal tubules of megalin knockout mice revealed that angiotensinogen protein was incorporated selectively in megalin-intact cells of the proximal tubule, indicating that the proximal tubule reabsorbs filtered angiotensinogen through megalin. Disruption of the filtration barrier in a transgenic mouse model of podocyte-selective injury increased renal angiotensin II content and markedly increased both tubular and urinary angiotensinogen protein without an increase in renal renin activity, supporting the dependency of renal angiotensin II generation on filtered angiotensinogen. Taken together, these data suggest that liver-derived angiotensinogen is the primary source of renal angiotensinogen protein and angiotensin II. Furthermore, an abnormal increase in the permeability of the glomerular capillary wall to angiotensinogen, which characterizes proteinuric kidney diseases, enhances the synthesis of renal angiotensin II.
authors.affiliation: Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan. taijim@is.icc.u-tokai.ac.jp
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.forename: Fumio
authors.initials: F
authors.lastname: Niimura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shimizu
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Iekuni
authors.initials: I
authors.lastname: Ichikawa
mesh_terms: D000804:Angiotensin II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000808:Angiotensinogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D012333:RNA, Messenger; D000808:Angiotensinogen; D000804:Angiotensin II