Loss of Primary Cilia Upregulates Renal Hypertrophic Signaling and Promotes Cystogenesis
- 1 May 2011
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 22 (5), 839-848
- https://doi.org/10.1681/asn.2010050526
Abstract
Primary cilia dysfunction alters renal tubular cell proliferation and differentiation and associates with accelerated cyst formation in polycystic kidney disease. However, the mechanism leading from primary ciliary dysfunction to renal cyst formation is unknown. We hypothesize that primary cilia prevent renal cyst formation by suppressing pathologic tubular cell hypertrophy and proliferation. Unilateral nephrectomy initiates tubular cell hypertrophy and proliferation in the contralateral kidney and provides a tool to examine primary cilia regulation of renal hypertrophy. Conditional knockout of the primary cilia ift88 gene leads to delayed, adult-onset renal cystic disease, which provides a window of opportunity to conduct unilateral nephrectomy and examine downstream kinetics of renal hypertrophy and cyst formation. In wild-type animals, unilateral nephrectomy activated the mTOR pathway and produced appropriate structural and functional hypertrophy without renal cyst formation. However, in ift88 conditional knockout animals, unilateral nephrectomy triggered increased renal hypertrophy and accelerated renal cyst formation, leading to renal dysfunction. mTOR signaling also increased compared with wild-type animals, suggesting a mechanistic cascade starting with primary ciliary dysfunction, leading to excessive mTOR signaling and renal hypertrophic signaling and culminating in cyst formation. These data suggest that events initiating hypertrophic signaling, such as structural or functional loss of renal mass, may accelerate progression of adult polycystic kidney disease toward end-stage renal disease.Keywords
This publication has 41 references indexed in Scilit:
- Rapamycin Ameliorates PKD Resulting from Conditional Inactivation of Pkd1Journal of the American Society of Nephrology, 2010
- Glomerulocystic kidney diseasePediatric Nephrology, 2010
- S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal hypertrophyAmerican Journal of Physiology-Renal Physiology, 2009
- Autosomal dominant polycystic kidney disease: the last 3 yearsKidney International, 2009
- Renal injury is a third hit promoting rapid development of adult polycystic kidney diseaseHuman Molecular Genetics, 2009
- Renal involvement in tuberous sclerosis complex and von Hippel–Lindau disease: shared disease mechanisms?Nature Reviews Nephrology, 2009
- Pkd1 Inactivation Induced in Adulthood Produces Focal Cystic DiseaseJournal of the American Society of Nephrology, 2008
- Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal ciliaHuman Molecular Genetics, 2008
- A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1Nature Medicine, 2007
- Disruption of Intraflagellar Transport in Adult Mice Leads to Obesity and Slow-Onset Cystic Kidney DiseaseCurrent Biology, 2007