title: IQGAP1 regulates actin cytoskeleton organization in podocytes through interaction with nephrin.
abstract: 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.
authors: Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China; Department of Nephrology, Qianfoshan Hospital, Shandong University, Jinan, China.
authors: Yipeng
authors: Y
authors: Liu
authors: Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
authors: Wei
authors: W
authors: Liang
authors: Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
authors: Yingjie
authors: Y
authors: Yang
authors: Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
authors: Yangbin
authors: Y
authors: Pan
authors: Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
authors: Qian
authors: Q
authors: Yang
authors: Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
authors: Xinghua
authors: X
authors: Chen
authors: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, Great Neck, NY, USA.
authors: Pravin C
authors: PC
authors: Singhal
authors: Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address: ghxding@gmail.com.
authors: Guohua
authors: G
authors: Ding
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D009401:Nephrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011692:Puromycin Aminonucleoside; D034622:RNA Interference; D017208:Rats, Wistar; D020703:ras GTPase-Activating Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: C101203:IQ motif containing GTPase activating protein 1; D008565:Membrane Proteins; C113267:nephrin; D020703:ras GTPase-Activating Proteins; D011692:Puromycin Aminonucleoside
keywords: Actin cytoskeleton; IQ domain GTPase-activating protein 1; Nephrin; Podocyte
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