Loss of primary cilia upregulates renal hypertrophic signaling and promotes cystogenesis

J Am Soc Nephrol. 2011 May;22(5):839-48. doi: 10.1681/ASN.2010050526. Epub 2011 Apr 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cilia / physiology*
  • Female
  • Glomerular Filtration Rate
  • Hypertrophy
  • Kidney / pathology*
  • Kidney Diseases, Cystic / etiology*
  • Male
  • Mice
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / physiology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology
  • Up-Regulation


  • Tg737Rpw protein, mouse
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases