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

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 (palladiniFBKO) were protected from kidney dysfunction and fibrosis, which were associated with reduced numbers of myofibroblasts compared to palladin floxed mice (palladinWT). 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.