Cystogenesis and elongated primary cilia in Tsc1-deficient distal convoluted tubules.
Tuberous sclerosis complex (TSC) is a multiorgan hamartomatous disease caused by loss of function mutations of either the TSC1 or TSC2 genes. Neurological symptoms of TSC predominate in younger patients, but renal pathologies are a serious aspect of the disease in older children and adults. To study TSC pathogenesis in the kidney, we inactivated the mouse Tsc1 gene in the distal convoluted tubules (DCT). At young ages, Tsc1 conditional knockout (CKO) mice have enlarged kidneys and mild cystogenesis with increased mammalian target of rapamycin complex (mTORC)1 but decreased mTORC2 signaling. Treatment with the mTORC1 inhibitor rapamycin reduces kidney size and cystogenesis. Rapamycin withdrawal led to massive cystogenesis involving both distal as well as proximal tubules. To assess the contribution of decreased mTORC2 signaling in kidney pathogenesis, we also generated Rictor CKO mice. These animals did not have any detectable kidney pathology. Finally, we examined primary cilia in the DCT. Cilia were longer in Tsc1 CKO mice, and rapamycin treatment returned cilia length to normal. Rictor CKO mice had normal cilia in the DCT. Overall, our findings suggest that loss of the Tsc1 gene in the DCT is sufficient for renal cystogenesis. This cytogenesis appears to be mTORC1 but not mTORC2 dependent. Intriguingly, the mechanism may be cell autonomous as well as non-cell autonomous and possibly involves the length and function of primary cilia.
Department of Neurology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37232, USA.
Eric A
EA
Armour
Robert P
RP
Carson
Kevin C
KC
Ess
D000375:Aging; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002923:Cilia / Q000502:physiology*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D007674:Kidney Diseases / Q000151:congenital / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000166:cytology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; C504923:Crtc2 protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C000624650:TSC1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C525637:rictor protein, mouse; D004247:DNA; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases