Histopathological analysis of renal cystic epithelia in thePkd2WS25/-mouse model of ADPKD

Thomson, Robert K.; Mentone, SueAnn; Kim, Robert; Earle, Karen; Delpire, Eric; Somlo, Stefan; Aronson, Peter S.

doi:10.1152/ajprenal.00153.2003

Cited by 59 publications

(50 citation statements)

References 35 publications

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“…It follows that polycystic kidney disease can result from defective ciliogenesis or from loss of discrete cilial proteins in otherwise apparently structurally normal cilia. Human ADPKD falls into the latter category (Thomson et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif

Geng

Okuhara

et al. 2006

Journal of Cell Science

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268

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Primary cilia play a key role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). The affected proteins, polycystin-1 (PC1) and polycystin-2 (PC2), interact with each other and are expressed in cilia. We found that COOH-terminal truncated PC2 (PC2-L703X), lacking the PC1 interaction region, still traffics to cilia. We examined PC2 expression in several tissues and cells lacking PC1 and found that PC2 is expressed in cilia independently of PC1. We used N-terminal deletion constructs to narrow the domain necessary for cilia trafficking to the first 15 amino acids of PC2 and identified a conserved motif, R6VxP, that is required for cilial localization. The N-terminal 15 amino acids are also sufficient to localize heterologous proteins in cilia. PC2 has endogenous cilia trafficking information and is present in cilia of cells lining cysts that result from mutations in PKD1.

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Section: Discussionmentioning

confidence: 99%

Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif

Geng

Okuhara

et al. 2006

Journal of Cell Science

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268

220

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“…Most flat cyst epithelial cells are negative for nephron segment markers and Na-K ATPase (45), suggesting that the morphological transition of Pkd1 -/-cyst epithelial cells is accompanied by loss of functional phenotype. However, expression of renal tubular markers within single cysts in Pkd1 -/-/LZ + kidneys was discontinuous.…”

Section: Discussionmentioning

confidence: 99%

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation

Nishio¹,

Hatano²,

Nagata³

et al. 2005

J. Clin. Invest.

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common human monogenic genetic disorder and is characterized by progressive bilateral renal cysts and the development of renal insufficiency. The cystogenesis of ADPKD is believed to be a monoclonal proliferation of PKD-deficient (PKD -/-) renal tubular epithelial cells. To define the function of Pkd1, we generated chimeric mice by aggregation of Pkd1 -/-ES cells and Pkd1 +/+ morulae from ROSA26 mice. As occurs in humans with ADPKD, these mice developed cysts in the kidney, liver, and pancreas. Surprisingly, the cyst epithelia of the kidney were composed of both

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“…Oocytes were fixed for 1 h in a solution containing 1% paraformaldehyde in 100 mM sodium phosphate, pH 7.4, and subsequently placed in holding buffer (100 mM phosphate with azide, 0.5% paraformaldehyde). Immunocytochemistry was then performed after tissue embedding and antigen retrieval as described previously (32). In brief, oocytes were embedded in Embed 812, cut into 1-m sections, etched for 5 min in a solution containing KOH (2 g), methanol (10 ml), and propylene oxide (5 ml), washed in methanol, and subjected to microwave antigen retrieval in citrate buffer (10 mM, pH 6.0).…”

Section: Methodsmentioning

confidence: 99%

Regulation of anion exchanger Slc26a6 by protein kinase C

Hassan

Mentone²,

Karniski³

et al. 2007

American Journal of Physiology-Cell Physiology

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(CFEX, PAT1) is an anion exchanger expressed in several tissues including renal proximal tubule, pancreatic duct, small intestine, liver, stomach, and heart. It has recently been reported that PKC activation inhibits A6-mediated Cl/HCO 3 exchange by disrupting binding of carbonic anhydrase to A6. However, A6 can operate in HCO 3-independent exchange modes of physiological importance, as A6-mediated Cl/ oxalate exchange plays important roles in proximal tubule NaCl reabsorption and intestinal oxalate secretion. We therefore examined whether PKC activation affects HCO 3-independent exchange modes of Slc26a6 functionally expressed in Xenopus oocytes. We found that PKC activation inhibited Cl/formate exchange mediated by Slc26a6 but failed to inhibit the related anion exchanger pendrin (SLC26A4) under identical conditions. PKC activation inhibited Slc26a6-mediated Cl/formate exchange, Cl/oxalate exchange, and Cl/Cl exchange to a similar extent. The inhibitor sensitivity profile and the finding that PMA-induced inhibition was calcium independent suggested a potential role for PKC-␦. Indeed, the PKC-␦-selective inhibitor rottlerin significantly blocked PMA-induced inhibition of Slc26a6 activity. Localization of Slc26a6 by immunofluorescence microscopy demonstrated that exposure to PKC activation led to redistribution of Slc26a6 from the oocyte plasma membrane to the intracellular compartment immediately below it. We also observed that PMA decreased the pool of Slc26a6 available to surface biotinylation but had no effect on total Slc26a6 expression. The physiological significance of these findings was supported by the observation that PKC activation inhibited mouse duodenal oxalate secretion, an effect blocked by rottlerin. We conclude that multiple modes of anion exchange mediated by Slc26a6 are negatively regulated by PKC-␦ activation.oxalate; formate; chloride; duodenum SLC26A6 (CFEX, PAT1) is a member of the SLC26 gene family of anion transporters and is expressed in many tissues including renal proximal tubule, pancreatic ducts, small intestine, liver, stomach, and heart (22,25,27,35,39,41). Functional expression studies have indicated that A6 can mediate multiple modes of anion exchange including Cl/formate, Cl/oxalate, Cl/HCO 3 , and Cl/OH exchanges (18,22,23,39,41). The physiological significance of A6 is indicated by defects in apical membrane Cl/base exchange in the proximal tubule and intestine of Slc26a6-null mice (6,17,40).Recent studies have begun to elucidate the molecular mechanisms regulating A6 transport activity. In particular, Cl/HCO 3 exchange activity of A6 is negatively regulated by ␣-adrenergic stimulation and angiotensin II, effects that are mediated by protein kinase C (PKC) activation (1, 2). Inhibition by PKC was attributed to PKC-mediated displacement of carbonic anhydrase II from binding to SLC26A6 and consequent disruption of the HCO 3 transport metabolon (2). Inhibition of A6 by PKC may explain the observation that agonists acting through PKC inhibit HCO 3 secretion in the pancreas (1...

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Histopathological analysis of renal cystic epithelia in thePkd2^WS25/-mouse model of ADPKD

Cited by 59 publications

References 35 publications

Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif

Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation

Regulation of anion exchanger Slc26a6 by protein kinase C

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