Sulfonylurea-Sensitive K+ Transport is Involved in Cl− Secretion and Cyst Growth by Cultured ADPKD Cells

Sullivan, Lawrence P.; Wallace, Darren P.; Gover, Tony D.; Welling, Paul A.; Yamaguchi, Tomohiro; Maser, Robin L.; Eppler, Jason W.

doi:10.1097/01.asn.0000034220.09301.9c

Cited by 19 publications

(20 citation statements)

References 31 publications

(39 reference statements)

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“…[14][15][16] Surprisingly, the subsequent enlargement of the cysts in the CRISP study appeared to be predictable within individual subjects. Semi-logarithmic plots of TCV and TKV versus time were linear suggesting that renal growth was exponential, similar to the growth of individual cysts formed by renal epithelial cells in culture [17][18][19] ( Figure S1). The purpose of this study was to reconcile the apparently chaotic process of cyst initiation and intrarenal cyst distribution with the orderly renal enlargement.…”

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confidence: 63%

Determinants of renal volume in autosomal-dominant polycystic kidney disease

Grantham

Cook

Torres

et al. 2008

Kidney International

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The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) recently showed that renal enlargement in autosomal-dominant polycystic kidney disease mimicked exponential growth. We determined the effects of cyst initiation rate, total number, and growth rate on the time-dependent change of total cyst volume (TCV). Mathematical models with equations integrating cyst surface area, volume, and an invariant growth rate constant were used to compute the time-dependent change in volume of solitary and multiple cysts. Multiple expanding cysts increased TCV in an exponential-like pattern even when individual cysts formed at different rates or exhibited different but constant growth rates. TCV depended on the rate of cyst initiation and on the total number of cysts; however, the compounding effect of exponential-like growth was the most powerful determinant of long-term cyst expansion. Extrapolation of TCV data plots for individual subjects back to an age of 18 predicted TCV values within an established range. We conclude that cysts started early in life were the main contributor to eventual TCV while their growth rate primarily determined renal size; although the rate of formation and the ultimate number of cysts also contributed. The good fit between the exponential models and the extrapolated CRISP data indicates that the TCV growth rate is a defining trait for individual patients and may be used as a prognostic marker.

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confidence: 63%

Determinants of renal volume in autosomal-dominant polycystic kidney disease

Grantham

Cook

Torres

et al. 2008

Kidney International

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“…Several primary pathogenetic mechanisms have been considered to be responsible for cyst formation, including: (a) abnormal regulation of epithelial cell proliferation (4-6); (b) abnormal transepithelial transport resulting in fluid accumulation in tubular lumina (7,8); and (c) remodeling of the ECM, leading to abnormal epithelial morphology, proliferation, and/or survival (9)(10)(11). Several signal transduction pathways are known to regulate epithelial cell expansion during kidney development, including those downstream of c-Ret (12) and of receptors for FGFs (13,14) and bone morphogenetic proteins (BMPs) (13).…”

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confidence: 99%

Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease

Qin¹,

Taglienti²,

Nauli³

et al. 2010

J. Clin. Invest.

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Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that is caused by mutations at two loci, polycystin 1 (PKD1) and polycystin 2 (PKD2). It is characterized by the formation of multiple cysts in the kidneys that can lead to chronic renal failure. Previous studies have suggested a role for hyperactivation of mammalian target of rapamycin (mTOR) in cystogenesis, but the etiology of mTOR hyperactivation has not been fully elucidated. In this report we have shown that mTOR is hyperactivated in Pkd1-null mouse cells due to failure of the HGF receptor c-Met to be properly ubiquitinated and subsequently degraded after stimulation by HGF. In Pkd1-null cells, Casitas B-lineage lymphoma (c-Cbl), an E3-ubiquitin ligase for c-Met, was sequestered in the Golgi apparatus with α 3 β 1 integrin, resulting in the inability to ubiquitinate c-Met. Treatment of mouse Pkd1-null cystic kidneys in organ culture with a c-Met pharmacological inhibitor resulted in inhibition of mTOR activity and blocked cystogenesis in this mouse model of ADPKD. We therefore suggest that blockade of c-Met is a potential novel therapeutic approach to the treatment of ADPKD.

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“…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 shortterm culture of Madin-Darby canine kidney (MDCK) cells (6)(7)(8)(9)(10)(11)(12) or cells from patients (13)(14)(15)(16)(17)(18) or PC1-null mice (19,20; for review, see ref. 21).…”

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confidence: 99%

Cyst formation following disruption of intracellular calcium signaling

Kuo¹,

DesRochers

Kimmerling

et al. 2014

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

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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...

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Sulfonylurea-Sensitive K+ Transport is Involved in Cl− Secretion and Cyst Growth by Cultured ADPKD Cells

Abstract: Abstract. Transepithelial chloride and fluid secretion by many types of epithelia involves activation of a conductive K ϩ

Cited by 19 publications

References 31 publications

Determinants of renal volume in autosomal-dominant polycystic kidney disease

Determinants of renal volume in autosomal-dominant polycystic kidney disease

Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease

Cyst formation following disruption of intracellular calcium signaling

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