# Autophagy in Polycystic Kidney Disease (PKD)

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2020 · —

## Abstract

Autophagy is a process that takes place in all eukaryotic cells that keeps cells alive under stressful conditions. In
autophagy there is the sequestration of damaged organelles into double-membraned autophagosomes that
subsequently fuse with lysosomes where their cargoes are delivered for degradation and recycling. In the healthy
kidney, autophagy plays an important role in the homeostasis and viability of renal tubular epithelial cells. There is
indirect evidence that PKD is a case of suppressed autophagy: 1) Many of the agents that protect against PKD are
autophagy inducers. 2) Preliminary/published data demonstrate decreased autophagic flux in Pkd1 -/- mouse
kidneys and PC1 -/- cells. 3) There is cross-talk between autophagy and apoptosis, a key process in cyst growth.
The overall hypothesis is that autophagic flux (autophagosome-lysosome fusion and degradation) is decreased
early in the polycystic kidney and that interventions that block autophagy will worsen PKD and conversely
autophagy inducers like caloric restriction, 2-deoxy-glucose or trehalose will increase autophagy, decrease
apoptosis and improve PKD in an autophagy–dependent manner. The presence of autophagy (autophagic flux,
presence of autophagosomes and autolysosomes), mitophagy (autophagosomes containing mitochondria) and
the effect of autophagy inhibition (using genetic techniques), autophagy induction (using autophagy-inducers that
are known to protect against PKD) on cyst growth and apoptosis will be determined in Pkd1 -/- mice and PKD1 -/-
cells. An improved understanding of the mechanism by which induction of autophagy can prevent PKD may lead
to the identification of new targets for both diagnosis and therapy of PKD. In Aim 1, the effect of autophagy
inhibition or induction in will be tested Pkd1 -/- mouse kidneys. Autophagic flux and apoptosis will be determined
during a time course in Pkd1 -/- mouse kidneys. It will be determined whether autophagy knockout in kidney-
specific double knockout ATG7, Pkd1 -/- mice worsens apoptosis, proliferation, PKD and kidney function. The
effect of autophagy inducers (caloric restriction, 2-deoxy-glucose or trehalose) on autophagy, apoptosis and
proliferation, PKD and renal function will be determined in Pkd1 -/- mice and ATG7, Pkd1 double knockout mice.
The effect of a novel autophagy inducer (trehalose) on PKD will be determined. In Aim 2, pathways of autophagy
in PKD1 -/- tubular cells will be determined. These experiments will use more sophisticated techniques of detection
of autophagic flux and mitophagy and pharmacological and genetic techniques of autophagy induction and
inhibition that cannot be performed in vivo. The effect of autophagy induction by mechanistically distinct methods
(glucose deprivation, trehalose, Beclin1 peptide) and autophagy inhibition (3 methyladenine, chloroquine,
expression of dominant negative ATG4) on autophagy pathways and flux, mitophagy, apoptosis, proliferation, cyst
size/number will be determined. ...

## Key facts

- **NIH application ID:** 9980175
- **Project number:** 5I01BX003803-03
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** CHARLES Louis EDELSTEIN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980175

## Citation

> US National Institutes of Health, RePORTER application 9980175, Autophagy in Polycystic Kidney Disease (PKD) (5I01BX003803-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9980175. Licensed CC0.

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