Kidney Week

Abstract: TH-PO1131

Fibroblast-Specific Palladin Drives Kidney Fibrosis via MRTF-SRF Signaling

Session Information

• CKD: Mechanisms, AKI, and Beyond - 1
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Yamamoto, Naoki, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Naoki Yamamoto, MD

• Sakai, Norihiko, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Norihiko Sakai, MD, PhD

• Yamamura, Yuta, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Yuta Yamamura, MD

• Ito, Kiyoaki, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Kiyoaki Ito, MD, PhD

• Mizushima, Ichiro, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Ichiro Mizushima, MD, PhD

• Hara, Akinori, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Akinori Hara, MD

• Shimizu, Miho, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Miho Shimizu, MD, PhD

• Wada, Takashi, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Takashi Wada, MD, PhD

• Iwata, Yasunori, Kanazawa Daigaku, Kanazawa, Ishikawa Prefecture, Japan

Yasunori Iwata, MD, PhD

Background

Fibrosis is a common end-stage pathway of progressive chronic kidney diseases. We previously demonstrated that myocardin-related transcription factor (MRTF)-serum response factor (SRF) signaling drives the expressions 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.

Methods

Proteome analysis using non-cancer lesion of renal cell carcinoma in 16 patients was performed to extract proteins that were strongly correlated with kidney function and fibrosis. After identifying a transforming growth factor (TGF)-β₁-inducible protein by stimulating renal fibroblasts with TGF-β₁, its functional experiments were performed in renal fibroblasts and murine model of adenine-induced kidney fibrosis. Additionally, human studies using kidney biopsy samples and publicly available databases were also explored.

Results

Proteome analysis showed that the actin cytoskeleton-regulating pathway was significantly correlated with estimated glomerular filtration rate (eGFR) and collagen type 1 alpha 1 expression. Of these, we found that palladin was one of the TGF-β₁-dependent actin-associated proteins in renal fibroblasts. 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 vivo, fibroblast-specific palladin-deficient mice (palladin^iFBKO) were protected from kidney dysfunction and fibrosis, which were associated with reduced numbers of myofibroblasts compared to palladin floxed mice (palladin^WT). In patients with kidney 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 was correlated with kidney function and fibrosis in patients with various kidney diseases.

Conclusion

Palladin builds profibrotic circuits of the palladin-MRTF-SRF axis through actin cytoskeleton reorganization. Fibroblast-specific palladin represents a novel therapeutic target for the treatment of progressive kidney diseases.

Funding

• Government Support – Non-U.S.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025adjdqhsm