Ciliar functions in the nephron

Rodat-Despoix, Lise; Delmas, Patrick

doi:10.1007/s00424-008-0632-0

Cited by 24 publications

(21 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A link between ciliary Ca 2+ signaling, the polycystin proteins, and cyst development has recently gained attention (42,(46)(47)(48)(49)(50)(51). The fact that the cilia in the InsP3R3 and PC2 knockdown cysts were still present, but absent in InsP3R1 knockdown cysts, by week 8, suggests that cilia may not be essential to the latter stages of cystogenesis and is broadly consistent with recent findings (52).…”

Section: Discussionsupporting

confidence: 81%

Cyst formation following disruption of intracellular calcium signaling

Kuo¹,

DesRochers

Kimmerling

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mutations in polycystin 1 and 2 (PC1 and PC2) cause the common genetic kidney disorder autosomal dominant polycystic kidney disease (ADPKD). It is unknown how these mutations result in renal cysts, but dysregulation of calcium (Ca 2+ ) signaling is a known consequence of PC2 mutations. PC2 functions as a Ca 2+ -activated Ca 2+ channel of the endoplasmic reticulum. We hypothesize that Ca 2+ signaling through PC2, or other intracellular Ca 2+ channels such as the inositol 1,4,5-trisphosphate receptor (InsP3R), is necessary to maintain renal epithelial cell function and that disruption of the Ca 2+ signaling leads to renal cyst development. The cell line LLC-PK1 has traditionally been used for studying PKD-causing mutations and Ca 2+ signaling in 2D culture systems. We demonstrate that this cell line can be used in long-term (8 wk) 3D tissue culture systems. In 2D systems, knockdown of InsP3R results in decreased Ca 2+ transient signals that are rescued by overexpression of PC2. In 3D systems, knockdown of either PC2 or InsP3R leads to cyst formation, but knockdown of InsP3R type 1 (InsP3R1) generated the largest cysts. InsP3R1 and InsP3R3 are differentially localized in both mouse and human kidney, suggesting that regional disruption of Ca 2+ signaling contributes to cystogenesis. All cysts had intact cilia 2 wk after starting 3D culture, but the cells with InsP3R1 knockdown lost cilia as the cysts grew. Studies combining 2D and 3D cell culture systems will assist in understanding how mutations in PC2 that confer altered Ca 2+ signaling lead to ADPKD cysts. primary cilia | polycysin 2 | calcium release T he commonly occurring genetic kidney disorder, autosomal dominant polycystic kidney disease (ADPKD), is the result of mutations in polycystin 1 or 2 (PC1 or PC2). The progressive cyst formation within all segments of the nephron that defines the disorder leads to renal failure requiring treatment by dialysis and/or organ transplantation (1-3). Altered Ca 2+ signaling is one of several pathways that have been implicated in the disease (4, 5). A major limitation toward elucidating the role of Ca 2+ signaling in cyst formation has been the lack of easily manipulated, physiologically relevant experimental methodologies.In the past, ADPKD research has relied largely upon data from mouse models and cells maintained in 2D cell culture. Mouse models have played a significant role in understanding the biology of cyst formation but are unable to fully recapitulate the physiology of disease progression in humans due to the inherent differences between the species including life span, genetics, and environment. Two-dimensional cell culture has the ability to provide information on signaling pathways and response to therapies in a fast, high-throughput manner, but is incapable of replicating the inherent 3D nature of cyst formation. Advances in 3D tissue culture over the past 2 decades have improved the ability to model cyst development in vitro. However, previously published 3D tissue models of ADPKD have relied upon shortter...

show abstract

Section: Discussionsupporting

confidence: 81%

Cyst formation following disruption of intracellular calcium signaling

Kuo¹,

DesRochers

Kimmerling

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Defects in ciliary biogenesis and function lead to diseases (collectively termed ciliopathies) that manifest with a subset of common phenotypes, including cystic kidneys, retinal dystrophies, cognitive impairment, and polydactyly [reviewed in (12)]. Like distal tubule cells, PT cells also express primary cilia, but no role for cilia in modulating PT ion transport has been described (12–14). …”

Section: Introductionmentioning

confidence: 99%

Flow stimulated endocytosis in the proximal tubule

Raghavan¹,

Weisz²

2015

Current Opinion in Nephrology and Hypertension

View full text Add to dashboard Cite

Purpose of review The proximal tubule (PT) plays a critical role in the reabsorption of ions, solutes and low molecular weight proteins from the glomerular filtrate. Although the PT has long been known to acutely modulate ion reabsorption in response to changes in flow rates of the glomerular filtrate, it has only recently been discovered that PT cells can similarly adjust endocytic capacity in response to flow. This review synthesizes our current understanding of mechanosensitive regulation of endocytic capacity in PT epithelia and highlights areas of opportunity for future investigations. Recent findings Recent studies have reported that the endocytic capacity of PT cells is dramatically increased upon exposure to flow and the accompanying fluid shear stress (FSS). Modulation of this pathway is dependent on increases in intracellular calcium [Ca2+]i initiated by bending of the primary cilium, and also requires purinergic receptor activation that is mediated by release of extracellular ATP. This article summarizes what is currently known about the signaling cascade that transduces changes in flow into alterations in endocytosis. We discuss the implications of this newly described regulatory pathway with respect to our understanding of protein retrieval by the kidney under normal conditions, and in diseases that present with low molecular weight proteinuria. Summary Primary cilia act as mechanotransducers that modulate apical endocytic capacity in PT cells in response to changes in fluid shear stress.

show abstract

“…It has been interpreted as an unsuccessful proliferative repair response of abnormal tubular cells degenerating into cyst formation. The abnormal behavior of the tubule in ADPKD patients origins from genetic ablation of a critical function of the polycystin proteins and primary cilia [6,7]. This system is supposed to act as a sensor for renal injury monitoring the urinary intratubular flux.…”

Section: Discussionmentioning

confidence: 99%