BACKGROUND: Inhibition of the renin-angiotensin system remains a cornerstone in reducing proteinuria and progression of kidney failure, effects believed to be the result of reduction in BP and glomerular hyperfiltration. However, studies have yielded conflicting results on whether podocyte-specific angiotensin II (AngII) signaling directly induces podocyte injury. Previous research has found that after AngII stimulation, β-arrestin-bound angiotensin II receptor type 1 (AT1R) is internalized in a clathrin- and dynamin-dependent manner, and that Dynamin1 and Dynamin2 double-knockout mice exhibit impaired clathrin-mediated endocytosis. METHODS: We used podocyte-specific Dyn double-knockout mice to examine AngII-stimulated AT1R internalization and signaling in primary podocytes and controls. We also examined the in vivo effect of AngII in these double-knockout mice through renin-angiotensin system blockers and through deletion of Agtr1a (which encodes the predominant AT1R isoform expressed in kidney, AT1aR). We tested calcium influx, Rac1 activation, and lamellipodial extension in control and primary podocytes of Dnm double-knockout mice treated with AngII. RESULTS: We confirmed augmented AngII-stimulated AT1R signaling in primary Dnm double-knockout podocytes resulting from arrest of clathrin-coated pit turnover. Genetic ablation of podocyte Agtr1a in Dnm double-knockout mice demonstrated improved albuminuria and kidney function compared with the double-knockout mice. Isolation of podocytes from Dnm double-knockout mice revealed abnormal membrane dynamics, with increased Rac1 activation and lamellipodial extension, which was attenuated in Dnm double-knockout podocytes lacking AT1aR. CONCLUSIONS: Our results indicate that inhibiting aberrant podocyte-associated AT1aR signaling pathways has a protective effect in maintaining the integrity of the glomerular filtration barrier.
BACKGROUND: Inhibition of the renin-angiotensin system remains a cornerstone in reducing proteinuria and progression of kidney failure, effects believed to be the result of reduction in BP and glomerular hyperfiltration. However, studies have yielded conflicting results on whether podocyte-specific angiotensin II (AngII) signaling directly induces podocyte injury. Previous research has found that after AngII stimulation, β-arrestin-bound angiotensin II receptor type 1 (AT1R) is internalized in a clathrin- and dynamin-dependent manner, and that Dynamin1 and Dynamin2 double-knockout mice exhibit impaired clathrin-mediated endocytosis. METHODS: We used podocyte-specific Dyn double-knockout mice to examine AngII-stimulated AT1R internalization and signaling in primary podocytes and controls. We also examined the in vivo effect of AngII in these double-knockout mice through renin-angiotensin system blockers and through deletion of Agtr1a (which encodes the predominant AT1R isoform expressed in kidney, AT1aR). We tested calcium influx, Rac1 activation, and lamellipodial extension in control and primary podocytes of Dnm double-knockout mice treated with AngII. RESULTS: We confirmed augmented AngII-stimulated AT1R signaling in primary Dnm double-knockout podocytes resulting from arrest of clathrin-coated pit turnover. Genetic ablation of podocyte Agtr1a in Dnm double-knockout mice demonstrated improved albuminuria and kidney function compared with the double-knockout mice. Isolation of podocytes from Dnm double-knockout mice revealed abnormal membrane dynamics, with increased Rac1 activation and lamellipodial extension, which was attenuated in Dnm double-knockout podocytes lacking AT1aR. CONCLUSIONS: Our results indicate that inhibiting aberrant podocyte-associated AT1aR signaling pathways has a protective effect in maintaining the integrity of the glomerular filtration barrier.
Authors: Fernanda M Cunha; Denise A Berti; Zulma S Ferreira; Clécio F Klitzke; Regina P Markus; Emer S Ferro Journal: J Biol Chem Date: 2008-07-10 Impact factor: 5.157
Authors: Monica Y Lee; Sean M Garvey; Alex S Baras; Julia A Lemmon; Maria F Gomez; Pamela D Schoppee Bortz; Guenter Daum; Renee C LeBoeuf; Brian R Wamhoff Journal: Hum Mol Genet Date: 2009-11-19 Impact factor: 6.150
Authors: Leo S Price; Michiel Langeslag; Jean Paul ten Klooster; Peter L Hordijk; Kees Jalink; John G Collard Journal: J Biol Chem Date: 2003-07-29 Impact factor: 5.157
Authors: Moin A Saleem; Jiri Zavadil; Maryse Bailly; Karen McGee; Ian R Witherden; Hermann Pavenstadt; Hsianghao Hsu; Julia Sanday; Simon C Satchell; Rachel Lennon; Lan Ni; Erwin P Bottinger; Peter Mundel; Peter W Mathieson Journal: Am J Physiol Renal Physiol Date: 2008-08-06
Authors: Xuefei Tian; Kazunori Inoue; Yan Zhang; Ying Wang; C John Sperati; Christopher E Pedigo; Tingting Zhao; Meihua Yan; Marwin Groener; Dennis G Moledina; Karen Ebenezer; Wei Li; Zhenhai Zhang; Dan A Liebermann; Lois Greene; Peter Greer; Chirag R Parikh; Shuta Ishibe Journal: JCI Insight Date: 2020-11-19