Study identifies myofibroblast autophagy as driver of cyst growth in polycystic kidney disease
Researchers have identified that autophagy — a cellular self-digestion process — within myofibroblasts plays a previously unrecognized role in driving cyst expansion and fibrosis in autosomal dominant polycystic kidney disease (ADPKD). The study used human ADPKD tissue, primary human renal myofibroblasts, and a mouse model, finding that genetically deleting the autophagy gene Atg5 in myofibroblasts significantly reduced cyst growth and improved kidney function without harming healthy kidneys. The findings suggest that targeting myofibroblast-specific autophagy or its upstream regulators — including a lactate-HIF1 signaling axis — could represent a new therapeutic strategy for ADPKD.
Autosomal dominant polycystic kidney disease (ADPKD), a leading genetic cause of kidney failure, is characterized by progressive cyst growth, fibrosis, and inflammation. While myofibroblasts (MFs) are known to accumulate around cysts and promote fibrosis, the cellular mechanisms underlying their pro-cystogenic activity were poorly understood. This study demonstrates that autophagy is elevated in MFs within both human and mouse ADPKD kidneys, and that inhibiting this process — either pharmacologically or by conditional deletion of the autophagy gene Atg5 in PDGFR-beta-expressing renal stromal cells — significantly reduces cyst growth, fibrosis, MF abundance, and improves kidney function in a mouse model. Critically, wild-type mice with the same Atg5 deletion showed no kidney abnormalities, suggesting the intervention may be selectively harmful to disease-driving cells. Metabolomic analysis further revealed that cyst epithelial cells secrete elevated lactate, which stabilizes hypoxia-inducible factor-1 (HIF1) in MFs, in turn upregulating autophagy-related genes and autophagic flux. This lactate-HIF1-autophagy axis in MFs then paracrinally stimulates cyst epithelial cell proliferation, creating a feed-forward loop that accelerates disease progression. The authors propose that targeting this pathway could offer a novel therapeutic avenue for slowing ADPKD.
What's missing
The study was conducted exclusively in male RC/RC mice, limiting conclusions about sex-dependent effects. The research does not address whether the lactate-HIF1-autophagy axis is specific to ADPKD or may also operate in other cystic kidney diseases. Long-term safety and efficacy of targeting myofibroblast autophagy in vivo have not been evaluated, and no human clinical or translational validation is presented.
What different sources said
- bioRxivCenter
Myofibroblast- specific autophagy drives cyst growth in autosomal dominant polycystic kidney disease
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