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Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
08:46

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium

Published on: September 1, 2015

Myofibroblast- specific autophagy drives cyst growth in autosomal dominant polycystic kidney disease

Abeda Jamadar, Viji Remadevi, Meekha M Varghese

    Biorxiv : the Preprint Server for Biology
    |June 22, 2026
    PubMed
    Abstract

    Insights

    Autophagy in myofibroblasts drives cyst growth and fibrosis in autosomal dominant polycystic kidney disease (ADPKD). Inhibiting this process may offer a new therapeutic strategy for ADPKD patients.

    Area of Science:

    • Nephrology
    • Cell Biology
    • Molecular Medicine

    Background:

    • Autosomal dominant polycystic kidney disease (ADPKD) is marked by cyst expansion, fibrosis, and inflammation, ultimately leading to kidney failure.
    • Myofibroblasts (MFs) contribute to ADPKD progression by promoting cyst growth and fibrosis, but the underlying cellular mechanisms are not fully understood.

    Purpose of the Study:

    • To investigate the role of autophagy within myofibroblasts in stimulating cyst expansion in ADPKD.
    • To elucidate the cellular mechanisms by which myofibroblast autophagy contributes to ADPKD pathogenesis.

    Main Methods:

    • Assessed autophagy in human ADPKD kidney tissue and primary human ADPKD renal myofibroblasts (ADPKD-MFs).
    • Utilized a mouse model (RC/RC) of ADPKD with conditional Atg5 deletion in myofibroblasts (RC/RC;Atg5KO).
    • Examined the effect of autophagy inhibition on ADPKD-MFs' paracrine stimulation of cyst epithelial cells and analyzed metabolomics of conditioned media.

    Main Results:

    • Autophagy was detected in myofibroblasts within human and mouse ADPKD kidneys.
    • Inhibition of autophagy in ADPKD-MFs reduced their pro-cystogenic paracrine activity.
    • RC/RC;Atg5KO mice exhibited decreased cyst growth, fibrosis, myofibroblast accumulation, and improved kidney function compared to controls.
    • Lactate in conditioned media stabilized HIF1α in myofibroblasts, promoting autophagy and supporting cyst epithelial cell growth.

    Conclusions:

    • Autophagy in myofibroblasts is a key driver of cyst expansion and fibrosis in ADPKD.
    • Lactate-mediated stabilization of HIF1α in myofibroblasts enhances autophagy, which is crucial for myofibroblast-driven cyst epithelial cell proliferation.
    • Targeting myofibroblast-specific autophagy presents a potential therapeutic avenue for managing ADPKD progression.

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