ESR 13: Inducing apoptosis in kidney cysts – A novel approach to curing Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most common monogenetic disease

Supervisor: Kai-Uwe Eckardt

PhD Student: Carlotta Pioppini

Short Summary

ADPKD is the most common hereditary renal disease occurring in 1:500 to 1:1000 individuals. ADPKD accounts for >90% of all hereditary renal cystic diseases, is predominantly caused by mutations in genes encoding for the proteins polycystin-1 and -2 (PKD1, 77%; PKD2, 15%). The most common manifestation is a continuous growth of multiple cysts in both kidneys leading to kidney failure in most affected individuals. However, Cyst initiation requires somatic second hit mutations, as ADPKD is recessive at the cellular level.

The only FDA approved therapy is Tolvaptan and it can only be prescribed for the treatment of patients with a high risk of fast progression. An advanced understanding of the pathways that promote cyst progression will hopefully identify and/or validate new targets for drug discovery leading to more targeted treatments for ADPKD patients. For these reasons, we will investigate this interface with the ultimate goal of identifying novel upstream and downstream targets to delay the progressive loss of kidney function due to cyst growth. The aim is to selectively induce apoptosis by decreasing cell viability in cyst lining cells and therefore to ameliorate the cystic phenotype in ADPKD.

Scientific strategy


We would like to get a better understanding of the deregulated molecular pathways that characterized the ADPKD. In particular, we want to have a deeper understanding of the role of HIF pathway and its downstream and upstream targets such as AspH as potential novel therapeutics targets to slow CKD progression in ADPKD.


(PKD1 KO) to test whether the inhibition of ASPH, specifically reduces Pkd1-deficient cells cell viability using a cell-based viability assay. A double PKD1/AspH knock-out mouse model will be created and murine read-out parameters (mice kidney function, kidney weight/body weight) will be measured and evaluated to determine the role of AspH in ADPKD progression. Furthermore, anti-cancer drug screening will be performed.

Expected Results:

We expect to better define and understand the role of downstream targets of HIF-1, especially AspH in ADPKD. This knowledge could be useful to identify and/or validate new targets for drug discovery leading to more targeted treatments for ADPKD patients.