Polycystic kidney disease affects 600,000 individuals in the US and is leading cause kidney failure and associated co-morbidities. It is inherited as an autosomal dominant trait and is characterized by the growth of fluid filled cysts that deform and can ultimately destroy the kidney. At the cellular level, somatic second hit events have been identified as initiating events for the growth of cysts. The goal of this proposal is to define the spectrum of mechanisms that determine cyst growth in human polycystic kidney disease. Our hypothesis is that while somatic inactivation of the PKD genes does give rise to cyst growth via cell autonomous mechanisms, non-cell autonomous factors acting locally and at a distance on tubule cells that retain expression of polycystins contribute to polycystic disease progression by either incorporating such cells into cysts or eliminating them so cysts can grow. We provide evidence that cysts in adult onset ADPKD can form by non-cell autonomous pathways. We used inducible conditional gene inactivation confined to the proximal tubule (PT) in adult mice and found that cysts also formed in distal nephron segments that still expressed polycystins. These non-cell autonomous cysts show increased proliferation and activation of the EGF receptor (EGFR) and of MAPK/ERK signaling pathways. In complementary studies, we found that perinatal inactivation of either Pkd gene, known to cause more rapid cyst growth, produce mosaic cysts that include a significant proportion of Pkd+/+ cells in addition to Pkd-/- cells. These data suggest that Pkd1-/- or Pkd2-/- cells not only form cysts but develop activities that impact otherwise normal cells and tubules both locally and at a distance. We will define the in vivo mechanisms of non-cell autonomous cyst formation in ADPKD by establishing the mechanism of disappearance of wild type cells in proximal tubule cysts and determining whether there are differential on wild type cells following inactivation of the Pkd genes in different nephron segments. We will also determine whether adult cysts formed following perinatal Pkd gene inactivation retain wild type cells. At a molecular level, we will define the mechanisms of EGFR and MAPK/ERK activation and their role in non-cell autonomous cyst formation. We will examine the in vivo effects of interfering with EGFR activation on growth of cysts still expressing polcysytins. We will determine whether EGFR activation is mediated by EGF ligand family members, and if so, which one and how is its production related to inactivation of polycystins. We will determine whether inactivation of the specific EGF ligand will abrogate non-cell autonomous cyst growth. In aggregate, these studies will define a more integrated understanding of the novel determinants of cyst progression in ADPKD and will provide data on whether targeting the non-cell autonomous cyst growth in ADPKD will be an effective therapy for improving progression of the disease.

Public Health Relevance

The growth of cysts that destroy the kidney in autosomal dominant polycystic kidney disease has been attributed to cells in the kidney that lose expression of polycystin genes. We have found that not only do these cells form cysts, but they provide signals to other cells that still have polycystin gene expression to also form cysts-a finding that has the potential to identify new targets for drug therapy for a disease which currently has none.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054053-07
Application #
8322016
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rasooly, Rebekah S
Project Start
1998-06-15
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$361,231
Indirect Cost
$143,731
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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