CST3 and GDF15 ameliorate renal fibrosis by inhibiting fibroblast growth and activation

The final strategies to care patients with end-stage renal fibrosis rely on dialysis and kidney transplantation. Because such treatments are invasive and cause health problems eventually, it is necessary to develop new therapeutic strategies for delaying the disease progress. We here searched for cytokines showing an anti-fibrotic activity in cell-based experiments. Cystatin C (CST3) and Growth differentiation factor 15 (GDF15) were identified to have anti-fibrotic activities in a cytokine array screening. In primary fibroblasts isolated from the mouse kidneys subjected to ureteral obstruction-induced fibrosis, each cytokine induced apoptotic cell death and reduced collagen production. These anti-fibrotic effects were further augmented by co-administration of both cytokines. Mechanistically, CST3 and GDF15 were found to block the TGF-β receptor and the N-Myc signaling pathways, respectively. In mice with unilateral ureter obstruction, each cytokine and the combination of two cytokines effectively reduced the fibrotic burden in the subjected kidneys. Therefore, we propose that CST3 and GDF15 could be potential candidates for biopharmaceutics to ameliorate renal fibrosis. •CST3 and GDF15 inhibit survival and collagen production of kidney fibroblasts.•CST3 inactivates fibroblasts by antagonizing the TGF-β-SMAD signaling pathway.•GDF15 inhibits the N-Myc induction in activated kidney fibroblasts.•Recombinant CST3 and GDF15 ameliorate kidney fibrosis in vivo.