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ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling
Heon Yung Gee, … , Edgar A. Otto, Friedhelm Hildebrandt
Heon Yung Gee, … , Edgar A. Otto, Friedhelm Hildebrandt
Published July 8, 2013
Citation Information: J Clin Invest. 2013;123(8):3243-3253. https://doi.org/10.1172/JCI69134.
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Research Article Article has an altmetric score of 17

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

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Abstract

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.

Authors

Heon Yung Gee, Pawaree Saisawat, Shazia Ashraf, Toby W. Hurd, Virginia Vega-Warner, Humphrey Fang, Bodo B. Beck, Olivier Gribouval, Weibin Zhou, Katrina A. Diaz, Sivakumar Natarajan, Roger C. Wiggins, Svjetlana Lovric, Gil Chernin, Dominik S. Schoeb, Bugsu Ovunc, Yaacov Frishberg, Neveen A. Soliman, Hanan M. Fathy, Heike Goebel, Julia Hoefele, Lutz T. Weber, Jeffrey W. Innis, Christian Faul, Zhe Han, Joseph Washburn, Corinne Antignac, Shawn Levy, Edgar A. Otto, Friedhelm Hildebrandt

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Figure 4

Effects of ARHGDIA knockdown on RHO GTPase activity and podocyte migration in cultured human podocytes.

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Effects of ARHGDIA knockdown on RHO GTPase activity and podocyte migrati...
(A) Active GTP-bound RAC1 and CDC42 precipitated from podocytes transfected with scrambled (Scr) or ARHGDIA siRNA using a GST-PAK1 (CRIB) pulldown assay. Ponceau red staining at the top shows the GST proteins used. Compared with control podoctyes, podocytes transfected with ARHGDIA siRNA exhibited a significant increase in relative RAC1 and CDC42 (168% and 185%, respectively). The efficiency of knockdown by siRNA was confirmed by immunoblotting with an anti-ARHGDIA antibody (second to lowest panel). (B) Active GTP-bound RHOA precipitated from podocytes transfected with scrambled or ARHGDIA siRNA using a GST-rhotekin (RBD) pulldown assay. Cells transfected with scrambled control siRNA versus ARHGDIA siRNA exhibited no significant difference in relative RHOA activity. A and B represent 3 experiments each. (C–E) Quantification of RAC1 (C), CDC42 (D), and RHOA (E) in ARHGDIA-depleted cells compared with control cells. Error bars indicate the SEM for greater than 4 independent experiments. *P < 0.05; **P < 0.01; difference from proteins in control podocytes transfected with scrambled siRNA. (F) Effect of ARHGDIA knockdown on podocyte migration. Podocytes transfected with ARHGDIA siRNA exhibited more active migration compared with those transfected with scrambled siRNA. Increase in podocyte migration by ARHGDIA knockdown (red) in serum-induced podocytes was reduced by 2 different RAC1 inhibitors (green). Error bars are shown in only one direction for clarity and indicate SDs for more than 4 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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