ESPN 51th Annual Meeting

ESPN 2018


 
POLYCYSTIN LEVELS REGULATE CELL DEATH-SURVIVAL RESPONSE DURING NUTRIENT STARVATION
JEAN-PAUL DECUYPERE 1 ST├ęPHANIE DE RECHTER 2 CAROLINE WEYDERT 1 ELKE BEHAEGHEL 1 PETER JANSSENS 1 BERT BAMMENS 3 RUDI VENNEKENS 4 DJALILA MEKAHLI 2

1- LABORATORY OF PEDIATRICS, DEPARTMENT OF DEVELOPMENT AND REGENERATION, KU LEUVEN, LEUVEN, BELGIUM
2- DEPARTMENT OF PEDIATRIC NEPHROLOGY, UNIVERSITY HOSPITALS LEUVEN, B3000 LEUVEN, BELGIUM
3- DEPARTMENT OF NEPHROLOGY, DIALYSIS AND RENAL TRANSPLANTATION, UNIVERSITY HOSPITALS, B3000 LEUVEN, BELGIUM
4- LABORATORY OF ION CHANNEL RESEARCH, DEPARTMENT OF CELLULAR AND MOLECULAR MEDICINE, KU LEUVEN, B3000 LEUVEN, BELGIUM
 
Introduction:

Autosomal dominant polycystic kidney disease (ADPKD) is the most common cystic kidney disease, caused by mutations in either PKD1 or PKD2, encoding for polycystin-1 (PC1) or polycystin-2 (PC2), respectively. The mechanism of cyst formation remains unknown. Renal ischemic injury or nephrotoxicity was proposed to enhance cystogenesis and explain the phenotypic variety between ADPKD patients. We therefore aimed to investigate the cellular response towards nutritional stress in mouse inner medullary collecting duct cells (IMCDs), either wild-type (WT) or lacking PC1 or PC2 (PC1KO or PC2KO), with a focus on cell survival (autophagy) and cell death (apoptosis).

Material and methods:

Autophagy was measured by assessing the number of autophagic vesicles (autophagosomes) using the autophagosome marker LC3-II and apoptosis was assessed by the levels of cleaved Caspase 3.

Results:

Basal autophagy appeared higher in mouse PC1KO versus WT IMCDs. In contrast, PC2KO IMCDs displayed reduced basal autophagy and an abolished autophagic response towards 3h nutrient starvation. However, after prolonged (48h) nutrient starvation, autophagy levels were higher in both PC1KO and PC2KO IMCDs compared to WT IMCDs. This was associated with less apoptosis after 72h of nutrient starvation and increased cell death resistance in PC1KO and PC2KO compared to WT IMCDs. Interestingly, PC1 levels increased, while PC2 levels reduced upon nutrient starvation in WT, but not in PC2KO and PC1KO IMCDs, respectively.

Conclusions:

Our data suggest that PC1 and PC2 interdependently regulate each other’s levels under nutrient starvation. This determines the cell death versus survival response during nutritional stress, in which PC1 favors a pro-apoptotic and PC2 a pro-autophagic response. We conclude that cells lacking functional PC1 or PC2 have an aberrant stress-induced regulation of PC1 and PC2 levels resulting in more cell survival during nutrient starvation than WT cells.