Increasing data has shown that the cytoskeletal reorganization of podocytes is involved in the onset of
proteinuria and the progression of glomerular disease.
Nephrin behaves as a signal sensor of the slit diaphragm to transmit cytoskeletal signals to maintain the unique structure of podocytes. However, the
nephrin signaling cascade deserves further study. IQGAP1 is a scaffolding
protein with the ability to regulate cytoskeletal organization. It is hypothesized that IQGAP1 contributes to actin reorganization in podocytes through interaction with
nephrin. IQGAP1 expression and IQGAP1-nephrin colocalization in glomeruli were progressively decreased and then gradually recovered in line with the development of foot process fusion and
proteinuria in
puromycin aminonucleoside-injected rats. In cultured human podocytes,
puromycin aminonucleoside-induced disruption of
F-actin and disorders of migration and spreading were aggravated by IQGAP1
siRNA, and these effects were partially restored by a wild-type IQGAP1 plasmid. Furthermore, the cytoskeletal disorganization stimulated by
cytochalasin D in COS7 cells was recovered by cotransfection with wild-type IQGAP1 and
nephrin plasmids but was not recovered either by single transfection of the wild-type IQGAP1 plasmid or by cotransfection of mutant IQGAP1 [△1443(S→A)] and wild-type
nephrin plasmids. Co-immunoprecipitation analysis using lysates of COS7 cells overexpressing
nephrin and each derivative-domain molecule of IQGAP1 demonstrated that the poly-
proline binding domain and RasGAP domain in the carboxyl terminus of IQGAP1 are the target modules that interact with
nephrin. Collectively, these findings showed that activated IQGAP1, as an intracellular partner of
nephrin, is involved in actin cytoskeleton organization and functional regulation of podocytes.