Autosomal Dominant Polycystic Kidney Disease (ADPKD)
and Nephronophthisis (NPH):
Primary Cilia and the Molecular Pathogenesis of
Cystic Kidney Disease
Hereditary cystic kidney diseases such as autosomal dominant polycystic kidney disease (ADPKD) or nephronophthisis (NPH) are among the most common causes of end stage renal failure worldwide. These diseases have been linked to mutations in genes encoding for proteins that localize to a specialized compartment of tubular renal epithelial cells, the primary cilium. Primary cilia are sensory organelles that project from the surface of almost all cells of the body and consist of a ciliary axoneme and the basal body/centriole which anchors the cilium in the cell body.
Different types of receptors have been found on primary cilia which seem to act as little antennae sensing the cell’s environment. It has been suggested that extracellular signals activate ciliary signaling to control cell cycle and regulate complex cellular programs such as apoptosis or differentiation. As part of the centrosomes of the mitotic spindle basal bodies/centrioles appear to play a crucial role in these processes. Various ciliary proteins also play a significant role in establishing planar cell polarity, thus enabling the renal tubular system to develop and maintain its unique structure.
Members of our team are working on various aspects of ciliary function, focussing on genetic cystic kidney disease (ADPKD, ARPKD, NPH). Our group was the first to show that proteins involved in the development of nephronophthisis (NPH) are located in monocilia of kidney cells. We could show that these NPH proteins form a multiprotein complex that is involved in signaling from cilia to the interior of the cell.
Members of our lab are addressing the function of the NPH protein complex in great detail, work on the identification of novel members of the protein complex using proteomics technologies, and address the in vivo relevance of protein interactions using the mouse and C. elegans as model systems.
Previously, we could show that the tumor suppressor Von-Hippel-Lindau disease gene product pVHL is a ciliary protein that is required for ciliogenesis and polarity signaling (see project "kidney cancer") in mammals. Analyzing Vhl-1 deficient worms revealed that loss of Vhl-1 without affecting ciliary function significantly increases the lifespan of this organism. We currently address a link between ciliary signaling, tissue regeneration and oncogenesis and characterize the role of miRNAs in this disease process.
Very recently, we found that the ciliary protein NPHP4 regulates Hippo signaling. The Hippo pathway has recently emerged as a potent regulator of cell proliferation and organ size. We found that NPHP4 promotes cell proliferation through the control of Hippo signaling. Loss of NPHP4 in NPH patients might result in hyperactive Hippo signaling and reduced pro-proliferative transcriptional activity. These changes might be critical in the pathogenesis of NPH characterized by small-sized kidneys and atrophic tubular epithelium. In contrast, loss of Hippo signaling activity might be associated with polycystic kidney diseases characterized by massive proliferation such as ADPKD.
