System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Ahead of print

PubMed: 41131992 DOI: 10.1002/path.6485

Fibroblast-specific palladin drives kidney fibrosis via MRTF-SRF signaling.

J Pathol

Authors: Naoki Yamamoto, Norihiko Sakai, Yuta Yamamura, Daichi Kaikoi, Daiki Hayashi, Takahiro Matsuno, Akihiko Koshino, Keisuke Sako, Keisuke Horikoshi, Takahiro Yuasa, Akira Tamai, Taichiro Minami, Megumi Oshima, Shiori Nakagawa, Shinji Kitajima, Akinori Hara, Miho Shimizu, Jumpei Terakawa, Shin-Ichi Horike, Takiko Daikoku, Atsushi Mizokami, Hiroko Ikeda, Moeno Kadoguchi, Hiroshi Arakawa, Sumio Ohtsuki, David Lagares, Takashi Wada, Yasunori Iwata

Affiliations

  • Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan.
  • Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan.
  • Graduate School of Veterinary Science, Azabu University, Sagamihara, Japan.
  • Laboratory of Toxicology, School of Veterinary Medicine, Azabu University, Sagamihara, Japan.
  • Division of Integrated Omics Research, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan.
  • Division of Animal Disease Model, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan.
  • Department of Integrative Cancer Therapy and Urology, Kanazawa University, Kanazawa, Japan.
  • Department of Diagnostic Pathology, Kanazawa University Hospital, Kanazawa, Japan.
  • Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
  • Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
  • Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Zenon Biotech, Boston, MA, USA.

Abstract

Fibrosis is a common end-stage pathway of progressive chronic kidney diseases. Previously we demonstrated that myocardin-related transcription factor (MRTF)-serum response factor (SRF) signaling drives the expression of fibrosis-related molecules through actin cytoskeleton dynamics in renal fibroblasts. However, it has not been elucidated whether actin-associated proteins relate to the pathogenesis of fibrosis. Here, we reveal that the actin cytoskeleton-regulating pathway is significantly correlated with estimated glomerular filtration rate (eGFR) and collagen type 1 alpha 1 expression in human proteome analysis. We found that palladin was one of the TGF-β1-dependent actin-associated proteins in renal fibroblasts. Our mechanistic studies demonstrated that palladin activates MRTF-SRF signaling via actin cytoskeleton rearrangement upon TGF-β1 stimulation. In addition, palladin expression itself was enhanced by MRTF-SRF signaling, indicating a positive feedback loop. In vitro, genetic silencing of the palladin-MRTF-SRF axis suppressed extracellular matrix production and myofibroblast differentiation. In preclinical models in vivo, fibroblast-specific palladin-deficient mice (palladin iFBKO) were protected from kidney dysfunction and fibrosis that developed in adenine-induced nephropathy, which was associated with reduced numbers of myofibroblasts compared to wild type (palladin F/F) mice. In patients with renal disease, palladin was significantly upregulated in the renal interstitium of patients with low eGFR and kidney fibrosis. Moreover, upregulation of the palladin-MRTF-SRF axis correlated with kidney function and fibrosis in patients with various kidney diseases, including IgA nephropathy, diabetic nephropathy, and nephrosclerosis. Taken together, we consider palladin to be a novel regulator of actin cytoskeleton signaling in fibrotic fibroblasts and represents a novel therapeutic target for the treatment of progressive kidney diseases. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

MeSH

Kidney Diseases, Actins, Myofibroblasts, Fibrosis, Diabetic Nephropathies, Cytoskeleton, Pathology, Kidney, Actin Cytoskeleton, Fibroblasts, Therapeutics