Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited renal failure and is caused by mutations two genes, PKD1 and PKD2. Based on the association of aneurysms and ADPKD it has been speculated that polycystins (PKD proteins) play an important role in maintaining blood vessel integrity. An endothelial cell defect has been implicated in this phenotype since Pkd null animals exhibit edema and hemorrhage. Despite the relevance of this problem, there is little known about the role that polycystins play in endothelial cells. We recently used Cre-Lox technology to induce an endothelial cell specific knock out of Pkd1 or Pkd2 in mice. We found that selective inactivation of either gene in endothelial cells yielded a subset of the vascular defects described in Pkd null embryos including ~30-40% perinatal lethality, occasional hemorrhage, polyhydramnios and placental abnormalities. Remarkably, these embryos lacked edema, which is a universal feature of all targeted Pkd null alleles. These studies demonstrated a functional role for polycystins in the endothelial cell compartment and prompted us to hypothesize that loss of functional polycystins results in dysregulation of endothelial cell related signaling pathways. n this application, we propose three specific aims that seek to develop a mechanistic understanding of the functional role that polycystins play in endothelial cells at both the cellula and whole animal level.
In Aim1 we will use Pkd null and conditional alleles to explore the basis of edema formation in Pkd1/Pkd2 mutant animals.
Aim 2 is based on our observation that polycystin depleted endothelial cells exhibit defective cell migration. We will conduct an in depth characterization of this phenotype using time-lapse imaging and biochemical methods. In addition we will use novel cellular biosensors to probe well-defined signaling pathways implicated in cell migration.
In Aim 3 we will employ comprehensive microarray studies of endothelial cells isolated from embryos at different gestational time points to infer the regulator networks that are disrupted in Pkd mutant endothelial cells in vivo. At the conclusion of these studies, we will have gained novel insights into how polycystins fit into the context of vascular development. The hope is that these fundamental paradigms will have broader implications for defining polycystin function, a subject that remains vaguely understood despite many years of intense investigation.
Autosomal dominant polycystic kidney disease (ADPKD) is a common form of inherited renal failure that is associated with blood vessel defects such as intracranial aneurysms. Despite the relevance of this problem, there is little known about the function of ADPKD genes in the vascular system. These studies will provide fundamental insights into the developmental role that ADPKD proteins play in endothelial cells, the major cell type that lines blood vessel walls.
|Kim, Seokho; Nie, Hongguang; Nesin, Vasyl et al. (2016) The polycystin complex mediates Wnt/Ca(2+) signalling. Nat Cell Biol 18:752-764|
|Wu, Xudong; Indzhykulian, Artur A; Niksch, Paul D et al. (2016) Hair-Cell Mechanotransduction Persists in TRP Channel Knockout Mice. PLoS One 11:e0155577|
|Cebotaru, Liudmila; Liu, Qiangni; Yanda, Murali K et al. (2016) Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease. Kidney Int 90:90-9|
|Ta, Michelle H T; Schwensen, Kristina G; Liuwantara, David et al. (2016) Constitutive renal Rel/nuclear factor-?B expression in Lewis polycystic kidney disease rats. World J Nephrol 5:339-57|
|Chapman, Arlene B; Devuyst, Olivier; Eckardt, Kai-Uwe et al. (2015) Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 88:17-27|
|Perrone, Ronald D; Malek, Adel M; Watnick, Terry (2015) Vascular complications in autosomal dominant polycystic kidney disease. Nat Rev Nephrol 11:589-98|
|Kurbegovic, Almira; Kim, Hyunho; Xu, Hangxue et al. (2014) Novel functional complexity of polycystin-1 by GPS cleavage in vivo: role in polycystic kidney disease. Mol Cell Biol 34:3341-53|
|Liu, Dongyan; Wang, Connie J; Judge, Daniel P et al. (2014) A Pkd1-Fbn1 genetic interaction implicates TGF-? signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 25:81-91|
|Tan, Matthew; Wettersten, Hiromi I; Chu, Kristy et al. (2014) Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels. Am J Physiol Renal Physiol 307:F1179-86|
|Fonseca, Jonathan M; Bastos, Ana P; Amaral, Andressa G et al. (2014) Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1-deficient mice. Kidney Int 85:1137-50|
Showing the most recent 10 out of 11 publications