The relevance of the hypoxia-inducible transcription factor HIF-1alpha for cyst growth in polycystic kidney disease

• Applicant: Privatdozent Dr. Björn Buchholz
• Subject Area: Nephrology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 237670502

Polycystic kidney diseases (PKD) are characterized by various bilateral renal cysts that often enlarge gradually over time which leads to compression of healthy kidney tissue. In case of ADPKD, the most common form of PKD, cyst enlargement results in a decline of kidney function and the need for renal replacement therapy in about 50% of the patients. Therefore, current clinical trials attempt to inhibit cyst growth presuming to retain kidney function. Cyst growth is largely driven by chloride-dependent fluid secretion across the cyst epithelium into the cyst lumen. Previously, we have shown, that polycystic kidneys are characterized by loco-regional hypoxia which leads to stabilization of the hypoxia-inducible transcription factor HIF-1alpha in the cyst epithelium. Preliminary data obtained from two different in vitro cyst models show, that stabilization of HIF-1alpha enhances cyst growth. In addition, HIF-1alpha induces calcium-activated luminal chloride secretion. We also found that both, the calcium-activated chloride channel anoctamin 6 (ANO6) and the purinergic receptor P2Y2R are regulated in a HIF-1alpha-dependent manner. Beyond that, ANO6 is localized in the primary cilium of renal tubular cells which further raises the question about its functional relevance in PKD which are all defined by structural or functional defects of the primary cilium. With this application and with regard to our preliminary data we want to determine the role of HIF-1alpha in a PKD1 orthologous mouse model. In addition, we want to study the relevance of ANO6 and P2Y2R for cyst secretion. Moreover, we want to study the functional role of ANO6 in the cilium. Our investigations could help to reveal the molecular mechanisms of renal cyst growth in order to find therapeutic strategies to inhibit cyst enlargement and preserve renal function in PKD.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Participating Persons: Professor Dr. Karl Kunzelmann; Professorin Dr. Dorien Peters