title: Rhophilin-1 is a key regulator of the podocyte cytoskeleton and is essential for glomerular filtration.
abstract: Rhophilin-1 is a Rho GTPase-interacting protein, the biologic function of which is largely unknown. Here, we identify and describe the functional role of Rhophilin-1 as a novel podocyte-specific protein of the kidney glomerulus. Rhophilin-1 knockout mice were phenotypically normal at birth but developed albuminuria at about 2 weeks of age. Kidneys from severely albuminuric mice revealed widespread podocyte foot process effacement, thickening of the glomerular basement membrane, and FSGS-like lesions. The absence of any overt changes in the expression of podocyte proteins at the onset of proteinuria suggested that the primary cause of podocyte abnormalities in Rhpn1-null mice was the result of cell-autonomous, Rhophilin-1-dependent signaling events. In culture, Rhophilin-1 was detected at the plasma membrane leading edge of primary podocytes, where it elicited remodeling of the actin cytoskeleton network. This effect of Rhophilin-1 on actin cytoskeleton organization associated with inhibitory effects on Rho-dependent phosphorylation of the myosin regulatory light chain and stress fiber formation. Conversely, phosphorylation of myosin regulatory light chain increased in podocyte foot processes of Rhpn1(-/-) mice, implicating altered actinomyosin contractility in foot process effacement and compromised filtration capacity. Targeted deletion of RhoA in podocytes of Rhophilin-1 knockout mice exacerbated the renal injury. Taken together, our results indicate that Rhophilin-1 is essential for the integrity of the glomerular filtration barrier and that this protein is a key determinant of podocyte cytoskeleton architecture.
authors: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics.
authors: Mark A
authors: MA
authors: Lal
authors: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics.
authors: Ann-Charlotte
authors: AC
authors: Andersson
authors: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics.
authors: Kan
authors: K
authors: Katayama
authors: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics.
authors: Ziejie
authors: Z
authors: Xiao
authors: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics.
authors: Masatoshi
authors: M
authors: Nukui
authors: Department of Laboratory Medicine, Division of Clinical Research Center, and.
authors: Kjell
authors: K
authors: Hultenby
authors: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors: Annika
authors: A
authors: Wernerson
authors: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karl.Tryggvason@ki.se.
authors: Karl
authors: K
authors: Tryggvason
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology*; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C097916:rhophilin
keywords: FSGS; albuminuria; glomerulus; podocyte