# Novel Roles of GDF15 in Alleviating Renal Fibrosis: Promoting Autophagy and Lysosome Biogenesis via Inhibition of the PI3K/Akt/mTOR Pathway

## TL;DR

This study shows that GDF15 protects against kidney fibrosis by boosting autophagy and lysosome activity through a specific signaling pathway.

## Contribution

The novel contribution is identifying GDF15's protective role in renal fibrosis via autophagy and lysosome biogenesis through the PI3K/Akt/mTOR pathway.

## Key findings

- GDF15 expression is downregulated in tubulointerstitial fibrosis.
- GDF15 promotes autophagy and lysosome biogenesis via the PI3K/Akt/mTOR pathway.
- Increased GDF15 reduces macrophage infiltration and mitigates renal fibrosis.

## Abstract

Tubulointerstitial fibrosis (TIF) significantly contributes to the development of end‐stage renal disease (ESRD) in chronic kidney disease (CKD). However, the underlying mechanisms driving its development remain poorly understood, thereby impeding the development of effective prevention and treatment strategies. Although growth differentiation factor 15 (GDF15) has been implicated in kidney diseases, its specific relationship and mechanisms in the context of renal TIF remain unclear. In this study, we investigated the role and mechanisms of GDF15 in TIF using a mouse model of unilateral ureteral obstruction (UUO) and human tubular epithelial cells (HK2) stimulated by transforming growth factor‐β1 (TGF‐β1). Our findings demonstrated a downregulation of GDF15 expression in TIF. The upregulation of GDF15 mitigates renal TIF and reduces macrophage infiltration, whereas its downregulation exacerbates these conditions. Further analysis revealed that GDF15 promotes autophagy and lysosome biogenesis via the PI3K/Akt/mTOR signalling pathway, conferring a protective effect against TIF. In summary, our study demonstrated a negative correlation between GDF15 expression and renal TIF, highlighting its protective role in TIF. Moreover, GDF15 was found to promote autophagy and resolution of TIF through the PI3K/Akt/mTOR signalling pathway.