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Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease

Nature Medicine volume 14, pages 1370–1376 (2008)Cite this article

Abstract

Blockade of mineralocorticoid receptor has been shown to improve the clinical outcomes of proteinuric kidney diseases1,2. However, little is known about the regulation of mineralocorticoid receptor–dependent transcriptional activity in renal disease. Here we identify a new role for Rac1, a member of the Rho family GTPases, as a potent activator of mineralocorticoid receptor signal transduction both in vitro and in vivo. Transient transfection assays in HEK 293 cells revealed that constitutively active Rac1 (CA-Rac1) enhanced mineralocorticoid receptor–dependent reporter activity, which was accompanied by increased nuclear translocation of mineralocorticoid receptor. CA-Rac1 facilitated mineralocorticoid receptor nuclear accumulation also in podocytes via p21-activated kinase phosphorylation. In mice lacking Rho GDP-dissociation inhibitor-α (Arhgdia−/− mice)3, renal abnormalities, including heavy albuminuria and podocyte damage, were associated with increased Rac1 (but not RhoA) and mineralocorticoid receptor signaling in the kidney, without alteration in systemic aldosterone status. Pharmacological intervention with a Rac-specific small-molecule inhibitor4,5 diminished mineralocorticoid receptor overactivity and renal damage in this model. Furthermore, albuminuria and histological changes in Arhgdia−/− mice were suppressed by mineralocorticoid receptor blockade, confirming the pathological role of Rac1-mineralocorticoid receptor interaction. Our results provide evidence that signaling cross-talk between Rac1 and mineralocorticoid receptor modulates mineralocorticoid receptor activity and identify Rac1 as a therapeutic target for chronic kidney disease.

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Figure 1: Active Rac1 enhances mineralocorticoid receptor (MR) transcriptional activity and nuclear translocation.
Figure 2: Renal damage, activity of Rho family GTPases and MR signaling in Arhgdia−/− mice.
Figure 3: Effects of NSC23766 on renal damage of Arhgdia−/− mice.
Figure 4: MR signaling mediates albuminuria and renal injury in Arhgdia−/− mice.

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Acknowledgements

We are grateful to S. Fukuda for help in electron microscopic analysis. We thank Pfizer for providing eplerenone and Asahi Kasei Pharma for providing fasudil.

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Author notes

  1. Shigeru Shibata and Miki Nagase: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Shigeru Shibata, Miki Nagase, Shigetaka Yoshida, Wakako Kawarazaki & Toshiro Fujita

  2. Department of Anatomy, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Hidetake Kurihara

  3. Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Hirotoshi Tanaka

  4. Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, Osaka, 537-8511, Japan

    Jun Miyoshi

  5. Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Yoshimi Takai

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Contributions

S.S. and M.N. planned and performed experiments and wrote the manuscript. S.Y. and W.K. helped with experimental procedures and contributed to data discussion. H.K. provided the podocyte cell line and advised on the technical proposal. H.T. provided mineralocorticoid receptor plasmids and advised on the experimental approach and writing. J.M. and Y.T. generated Arhgdia−/− mice, provided expression plasmids containing wild-type and mutant Rho GTPases, advised on the experimental approach and contributed to data discussion. T.F. planned and directed the project and reviewed the manuscript.

Corresponding author

Correspondence to Toshiro Fujita.

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Shibata, S., Nagase, M., Yoshida, S. et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med 14, 1370–1376 (2008). https://doi.org/10.1038/nm.1879

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