Primary cilia and kidney injury: current research status and future perspectives

Wang, S.; Dong, Zheng

doi:10.1152/ajprenal.00399.2013

Cited by 49 publications

(56 citation statements)

References 228 publications

(176 reference statements)

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“…Cilium length is mainly determined by IFT particles, coordinated by kinesin-2 complex and dynein proteins, although in mammalian cells nonIFT regulators of cilia have been identified. 13 KIF3A plays a major part in Figure 3. Autophagy activation increases cilium length.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 It is now recognized that primary cilia not only contribute to cellular sensing but are involved in cell proliferation, differentiation, apoptosis, endocytosis/exocytosis, and planar cell polarity. [8][9][10][11][12][13] Cilium may be a hub for cellular signaling integration, on which certain key molecules from the WNT, notch, and hedgehog pathways have been localized.…”

Section: Introductionmentioning

confidence: 99%

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Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways

Wang¹,

Livingston

et al. 2015

Autophagy

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118

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Abbreviations: 3-MA, 3-methyladenine; ANKS6, ankyrin repeat and sterile a motif domain containing 6; ATG/atg, autophagy-related; Baf, bafilomycin A 1 ; DAPI, 4 0 -6-diamidino-2-phenylindole; Ac-TUBA, acetylated-tubulin a; CQ, chloroquine; CF, confluence; FBS, fetal bovine serum; HK2, human kidney proximal tubular cells; IFT, intraflagellar transport; K D , knockdown; KAP3, kinesin family-associated protein 3; KIF3A/3B, kinesin family member 3A/3B; KO, knockout; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; LTA, lotus tetragonolobus agglutinin; MEF, mouse embryonic fibroblast; MTOR, mechanistic target of rapamycin; OFD1, oral-ficial-digital syndrome 1; PBS, phosphate-buffered saline; PKD, polycystic kidney disease; Rapa, rapamycin; RKRB, Krebs-Henseleit saline containing 25 mM NaHCO 3 ; RPS6KB1, ribosomal protein S6 kinase; 70kDa, polypeptide 1; SD, standard deviation.Primary cilium is an organelle that plays significant roles in a number of cellular functions ranging from cell mechanosensation, proliferation, and differentiation to apoptosis. Autophagy is an evolutionarily conserved cellular function in biology and indispensable for cellular homeostasis. Both cilia and autophagy have been linked to different types of genetic and acquired human diseases. Their interaction has been suggested very recently, but the underlying mechanisms are still not fully understood. We examined autophagy in cells with suppressed cilia and measured cilium length in autophagy-activated or -suppressed cells. It was found that autophagy was repressed in cells with short cilia. Further investigation showed that MTOR activation was enhanced in cilia-suppressed cells and the MTOR inhibitor rapamycin could largely reverse autophagy suppression. In human kidney proximal tubular cells (HK2), autophagy induction was associated with cilium elongation. Conversely, autophagy inhibition by 3-methyladenine (3-MA) and chloroquine (CQ) as well as bafilomycin A 1 (Baf) led to short cilia. Cilia were also shorter in cultured atg5-knockout (KO) cells and in atg7-KO kidney proximal tubular cells in mice. MG132, an inhibitor of the proteasome, could significantly restore cilium length in atg5-KO cells, being concomitant with the proteasome activity. Together, the results suggest that cilia and autophagy regulate reciprocally through the MTOR signaling pathway and ubiquitin-proteasome system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways

Wang¹,

Livingston

et al. 2015

Autophagy

Self Cite

118

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“…and cAMP in the renal tubular epithelial cells of pcy mice. Morphology and function of cilia in zebrafish with ciliopathy may be improved by the administration of rapamycin and rescovitine [25,26]; however, applicability to human NPHP is unknown. Living-donor kidney transplantation was found to have favorable outcome in many reports including the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) [27].…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic characteristics of Japanese nephronophthisis patients

et al. 2015

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Background Nephronophthisis (NPH) accounts for 4-5 % of end-stage renal disease occurring in childhood. Method We investigated the clinical context and characteristics of renal and extrarenal symptoms, as well as the NPHP genes, in 35 Japanese patients with clinical and histologic features suggesting NPH. Results NPH occurred fairly uniformly throughout Japan irrespective of region or gender. In three families, NPH affected siblings. The median age of patients was 12.5 years. Renal abnormalities attributable to NPH discovered through mass screening, such as urine tests in school. However, NPH accounted for less than 50 % of children with abnormal findings, including incidentally discovered renal dysfunction during evaluation of extrarenal symptoms or during routine check-ups. Typical extrarenal manifestations leaded to discovery including anemia and delayed physical development. The urine often showed low gravity specific density and low molecular weight proteinuria. Frequent renal histologic findings included cystic dilation of tubules, mainly in the medulla, and irregularity of tubular basement membranes. Genetically abnormalities of NPHP1 were not common, with large deletions frequently noted. Compound heterozygotes showing single abnormalities in each of NPHP1, NPHP3, and NPHP4 were observed. Conclusions Our findings resemble those reported in Western populations.

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“…This increase in apoptosis is in accord with the increased rate of cell death associated with primary cilia defects in in vitro and animal models of ciliopathies (3,11,15) and supports the notion of the role of the primary cilium in cell survival signaling. Loss of cilia was also proposed to lead to increased apoptotic sensitivity in certain cell culture model systems as well (43), whereas shortening of cilia enhanced the sensitivity of cultured epithelial cells to injury cues (42). To our knowledge, this is the first report to link primary cilia signaling and epithelial extrusion, and further studies are warranted.…”

Section: Discussionmentioning

confidence: 74%

The exocyst gene Sec10 regulates renal epithelial monolayer homeostasis and apoptotic sensitivity

Polgár

Lee

Lui

et al. 2015

American Journal of Physiology-Cell Physiology

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Polgar N, Lee AJ, Lui VH, Napoli JA, Fogelgren B. The exocyst gene Sec10 regulates renal epithelial monolayer homeostasis and apoptotic sensitivity. Am J Physiol Cell Physiol 309: C190-C201, 2015. First published June 3, 2015; doi:10.1152/ajpcell.00011.2015.-The highly conserved exocyst protein complex regulates polarized exocytosis of subsets of secretory vesicles. A previous study reported that shRNA knockdown of an exocyst central subunit, Sec10 (Sec10-KD) in Madin-Darby canine kidney (MDCK) cells disrupted primary cilia assembly and 3D cyst formation. We used three-dimensional collagen cultures of MDCK cells to further investigate the mechanisms by which Sec10 and the exocyst regulate epithelial polarity, morphogenesis, and homeostasis. Sec10-KD cysts initially demonstrated undisturbed lumen formation although later displayed significantly fewer and shorter primary cilia than controls. Later in cystogenesis, control cells maintained normal homeostasis, while Sec10-KD cysts displayed numerous apoptotic cells extruded basally into the collagen matrix. Sec10-KD MDCK cells were also more sensitive to apoptotic triggers than controls. These phenotypes were reversed by restoring Sec10 expression with shRNA-resistant human Sec10. Apico-basal polarity appeared normal in Sec10-KD cysts, whereas mitotic spindle angles differed significantly from controls, suggesting a planar cell polarity defect. In addition, analysis of renal tubules in a newly generated kidney-specific Sec10-knockout mouse model revealed significant defects in primary cilia assembly and in the targeted renal tubules; abnormal epithelial cell extrusion was also observed, supporting our in vitro results. We hypothesize that, in Sec10-KD cells, the disrupted exocyst activity results in increased apoptotic sensitivity through defective primary cilia signaling and that, in combination with an increased basal cell extrusion rate, it affects epithelial barrier integrity and homeostasis. exocyst; primary cilium; apoptosis; cell extrusion; epithelial monolayer DURING EMBRYONIC DEVELOPMENT, regeneration, and wound healing, epithelial sheets are reshaped to form novel, more complex structures through a process called epithelial morphogenesis. The resulting epithelial tissues serve as barriers that protect against the environment and separate different physiological compartments. To function as an effective barrier, epithelia need to maintain homeostasis after differentiation and morphogenesis. Epithelial polarity, morphogenesis, and homeostasis all require targeted delivery of specific proteins and membrane components to distinct regions of the plasma membrane. The exocyst, a highly conserved protein complex, is responsible for the targeting and tethering of membrane-bound vesicles before their soluble N-ethylmaleimide-sensitive fusion attachment protein receptor-mediated exocytosis at certain sites of the plasma membrane (13,38,50). This 750-kDa complex is composed of eight subunits: Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84. A central component ...

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Primary cilia and kidney injury: current research status and future perspectives

Abstract: Wang S, Dong Z. Primary cilia and kidney injury: current research status and future perspectives.

Cited by 49 publications

References 228 publications

Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways

Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways

Clinical and genetic characteristics of Japanese nephronophthisis patients

The exocyst gene Sec10 regulates renal epithelial monolayer homeostasis and apoptotic sensitivity

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