| First Author | Lal MA | Year | 2015 |
| Journal | J Am Soc Nephrol | Volume | 26 |
| Issue | 3 | Pages | 647-62 |
| PubMed ID | 25071083 | Mgi Jnum | J:276466 |
| Mgi Id | MGI:6316493 | Doi | 10.1681/ASN.2013111195 |
| Citation | Lal MA, et al. (2015) Rhophilin-1 is a key regulator of the podocyte cytoskeleton and is essential for glomerular filtration. J Am Soc Nephrol 26(3):647-62 |
| abstractText | 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. |
