Decreasing the viability of cyst-lining cells via inhibition of Ire1α as a novel strategy to treat autosomal-dominant polycystic kidney disease (ADPKD)

• Applicant: Dr. Matteus Krappitz
• Subject Area: Nephrology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438180007

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting 1:400 to 1:1,000 individuals. It accounts for over 90% of all hereditary renal cystic diseases and is characterized by the presence of bilateral renal cysts. These cysts typically grow and expand slowly over decades, resulting in significantly increased total kidney volume, progressive renal injury and ultimately end stage renal disease (ESRD) around the sixth decade of life. The most common extrarenal manifestation of ADPKD is polycystic liver disease, which can also occur as an independent genetic entity, autosomal-dominant polycystic liver disease (ADPLD). Previously, it has been demonstrated that ADPLD and ADPKD share a common underlying molecular genetic mechanism centered on the activity of polycystin-1 (PC1) despite differential degree of kidney manifestations. PC1 is the protein product of the primary gene linked to ADPKD, Pkd1. ADPKD appears to be recessive at the cellular level. Therefore, somatic second hits in the normal PC1-allele of cells containing the germline mutation initiate or accelerate the formation of cysts. It became evident that the Ire1α-XBP1 pathway, the most conserved branch of the endoplasmic reticulum (ER) unfolded protein response (UPR), plays a protective role in cyst formation induced by Sec63 deficiency, one of the genes causing ADPLD. This is accomplished by an optimization of the ER-folding environment of misfolded PC1 via upregulation of chaperone proteins dependent on XBP1. Our recent unpublished data has revealed that XBP1 is a direct genetic interactor of Pkd1 and may surprisingly promote the progression of ADPKD via inactivation of PC1. We hypothesize that upregulation of XBP1 protects Pkd1-deficient cyst cells from apoptosis, which in turn promotes cyst growth. Consequently, double inactivation of Pkd1/XBP1 leads to specific apoptosis of cyst lining epithelia without any impact on proliferation. Preliminary data strongly suggests that avenues modulating homeostatic Ire1α-XBP1 signaling in vivo may hold therapeutic potential. This protective effect is accomplished by selectively promoting the apoptosis of cells that have acquired second hits in Pkd1, and which are responsible for the development of cystic lesions that eventually lead to polycystic kidney and liver disease. Based on these studies the aim of this project is to investigate: a) the underlying mechanism of Ire1α-XBP1-double knockout dependent cyst-lining cell apoptosis and the impact of chemical modulation of the Ire1α-XBP1 pathway on cyst progression and b) the effect of XBP1 inactivation on the progression of polycystic liver disease due to Pkd1 or Pkhd1 deletion. We hypothesize that avenues that inhibit Ire1α-XBP1 hold therapeutic potential for a novel treatment of ADPKD.

• DFG Programme: Research Grants