Ion Channels in Renal Disease

Kuo, Ivana Y.; Ehrlich, Barbara E.

doi:10.1021/cr3001077

Cited by 29 publications

(21 citation statements)

References 183 publications

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“…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)(2)(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.…”

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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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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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“…However, little is known about how TRP channels transduce stimuli into channel activity, and the structural changes governing TRP channel gating remain unclear. PC2, a member of the TRPP family, has the same overall architecture as other TRP family channels, with 6 transmembrane domains and cytoplasmic N‐ and C‐terminal tails (7). Four PC2 units are believed to oligomerize as a tetramer to form a functional channel.…”

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The number and location of EF hand motifs dictates the calcium dependence of polycystin‐2 function

Kuo

Keeler²,

Corbin³

et al. 2014

FASEB j.

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Polycystin 2 (PC2) is a calcium-dependent calcium channel, and mutations to human PC2 (hPC2) are associated with polycystic kidney disease. The C-terminal tail of hPC2 contains 2 EF hand motifs, but only the second binds calcium. Here, we investigate whether these EF hand motifs serve as a calcium sensor responsible for the calcium dependence of PC2 function. Using NMR and bioinformatics, we show that the overall fold is highly conserved, but in evolutionarily earlier species, both EF hands bind calcium. To test whether the EF hand motif is truly a calcium sensor controlling PC2 channel function, we altered the number of calcium binding sites in hPC2. NMR studies confirmed that modified hPC2 binds an additional calcium ion. Single-channel recordings demonstrated a leftward shift in the calcium dependence, and imaging studies in cells showed that calcium transients were enhanced compared with wild-type hPC2. However, biophysics and functional studies showed that the first EF hand can only bind calcium and be functionally active if the second (native) calcium-binding EF hand is intact. These results suggest that the number and location of calcium-binding sites in the EF hand senses the concentration of calcium required for PC2 channel activity and cellular function.

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“…Furthermore, toxins are not filtered out from the blood and accumulated in the body. When the dysfunction of kidneys occurs partially or completely, the normal body performances are altered resulting in some serious health issues with confusing etiology such as chronic kidney disease of unknown etiology (CKDu) [19][20][21].…”

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confidence: 99%

Exploring the Root Cause for Chronic Kidney Disease of Unknown Etiology (CKDu) via Analysis of Metal Ion and Counterion Contaminants in Drinking Water: A Study in Sri Lanka

Perera

Dayananda

Liyanage

2020

Journal of Chemistry

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The introduction of elevated amounts of foreign ions into the blood may lead to impairment of the filtration membrane of kidneys and chronic kidney damage. In order to assess the risk of consumption of drinking water (dug well water) in chronic kidney disease of unknown etiology (CKDu), affected areas in Sri Lanka, trace metals, and other counterions in water samples obtained from dug wells were analyzed and compared with a reference area. Drinking water could be the major source that is responsible for entering nephrotoxic ion contaminants into the human body. To achieve the objective, drinking water samples were collected from dug wells in two CKDu endemic areas and a reference area where no CKDu patients were found in a dry season. In the Wewelketiya area (one of the endemic areas), Cd concentrations in 60% of water samples and Pb concentrations in 40% of water samples have exceeded the maximum limit given by Sri Lanka water quality standards. Fluoride concentrations also have exceeded the permissible limits of more than 80% of collected water samples in both CKDu endemic areas. However, none of the water samples in reference areas has reported that Cd, Pb, and fluoride are beyond their maximum permissible limits. Hence, people in the particular CKDu endemic areas are at risk of kidney tissue damage due to long-term exposure to drinking water with elevated levels of some metal ions and counterions.

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Ion Channels in Renal Disease

Cited by 29 publications

References 183 publications

Cyst formation following disruption of intracellular calcium signaling

Cyst formation following disruption of intracellular calcium signaling

The number and location of EF hand motifs dictates the calcium dependence of polycystin‐2 function

Exploring the Root Cause for Chronic Kidney Disease of Unknown Etiology (CKDu) via Analysis of Metal Ion and Counterion Contaminants in Drinking Water: A Study in Sri Lanka

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