Interdependent Regulation of Polycystin Expression Influences Starvation-Induced Autophagy and Cell Death

Area of Science:

• Nephrology
• Cell Biology
• Genetics

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder often caused by mutations in polycystin-1 (PC1) or polycystin-2 (PC2).
• Altered autophagy, a cellular degradation process, is increasingly recognized in ADPKD pathogenesis, but its precise regulation by PC1 and PC2 is not fully understood.

Purpose of the Study:

• To investigate the role of PC1 and PC2 in regulating autophagy and cell death/survival under nutritional stress in ADPKD models.
• To clarify how PC1 and PC2 influence cellular responses to starvation in the context of ADPKD.

Main Methods:

• Utilized mouse inner medullary collecting duct cells (mIMCDs) with PC1 or PC2 knockout (KO) and wild-type (WT) controls.
• Examined human urine-derived proximal tubular epithelial cells (PTEC) from ADPKD patients with PC1 mutations and healthy individuals.
• Assessed autophagy levels and cell death/survival rates under basal and starvation conditions, including experiments with autophagy inhibition and PC1/PC2 manipulation.

Main Results:

• PC1 deficiency led to enhanced basal and starvation-induced autophagy, correlating with reduced cell death.
• Autophagy inhibition normalized the enhanced cell death resistance in PC1-deficient cells, indicating PC1's role in promoting autophagic survival.
• PC2 deficiency showed altered autophagy dynamics, with increased autophagy and reduced cell death upon chronic starvation, which was reversible by PC1 reintroduction.

Conclusions:

• PC1 levels are critical in determining the switch between renal cell survival and death pathways, particularly under nutritional stress.
• PC1 deficiency enhances cellular survival in ADPKD by promoting autophagy, offering a potential therapeutic target.
• PC1 and PC2 expression are interconnected, influencing ADPKD cell fate during nutrient deprivation.