Kidney Week

Abstract: FR-OR11

Renal Myofibroblasts Undergo Autophagy to Support Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Basic and Translational Research
  October 25, 2024 | Location: Room 23, Convention Center
  Abstract Time: 04:40 PM - 04:50 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Jamadar, Abeda, The University of Kansas Medical Center, Kansas City, Kansas, United States

Abeda Jamadar, PhD

• Remadevi, Viji, The University of Kansas Medical Center, Kansas City, Kansas, United States

Viji Remadevi, PhD

• Rao, Reena, The University of Kansas Medical Center, Kansas City, Kansas, United States

Reena Rao, PhD

Background

Myofibroblasts often surround renal epithelial cysts in autosomal dominant polycystic kidney disease (ADPKD). Our previous studies showed that myofibroblast depletion ameliorates disease progression in the RC/RC mouse model of ADPKD. Based on our observation that myofibroblasts in ADPKD kidneys undergo autophagy, we examined if autophagy in myofibroblasts contributes to renal cyst growth in ADPKD.

Methods

Cell proliferation of human ADPKD renal cyst epithelial cells exposed to cell culture conditioned media from human ADPKD myofibroblasts treated with vehicle or autophagy inhibitor- chloroquine was measured. Autophagy protein 5 (ATG5) is crucial for autophagy. We made myofibroblast-specific Atg5 gene knockout- RC/RC;Atg5^f/f;PDGFRb^creER^T2 mouse by breeding RC/+;PDGFRb^cre-ER^T2 mouse with Atg5^f/f mice. Wild type (WT), Atg5KO; RC/RC, RC/RC:Atg5KO mouse littermates were treated with vehicle or tamoxifen and sacrificed at 28 weeks of age and their kidneys were analyzed.

Results

Immunofluorescence staining in human ADPKD kidneys and RC/RC mouse kidneys showed that myofibroblasts surrounding renal cysts undergo autophagy. Human ADPKD renal cyst epithelial cells exposed to human ADPKD renal myofibroblast-conditioned media proliferated more compared to cells exposed to control media. Inhibition of autophagy in ADPKD human-renal myofibroblasts reduced the ability of their conditioned media to induce cyst epithelial cell proliferation in vitro. RC/RC:Atg5KO group had significantly lower kidney/body weight ratio, cyst number and cystic index when compared to RC/RC group. RC/RC:Atg5KO group had significantly reduced fibrosis and extracellular matrix related gene expression when compared to RC/RC group. No morphological changes were observed in Atg5KO mice when compared to WT.

Conclusion

Our results suggest that myofibroblasts in ADPKD kidneys undergo autophagy to support cyst growth, and inhibition of autophagy in renal myofibroblasts leads to reduced renal cyst growth and fibrosis.

Funding

• NIDDK Support