Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres, Vicente E.; Harris, Peter C.

doi:10.1681/asn.2013040398

Cited by 239 publications

(239 citation statements)

References 164 publications

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“…For example, it is known that the different isoforms of the InsP3R respond to elevation in cAMP, and hence to PKA phosphorylation, in distinct patterns that potentially fulfill functionally alternate roles (56)(57)(58). Additionally, the subcellular distribution of InsP3R and PC2 can differ, providing another aspect that may alter Ca 2+ signaling in distinct regions of a cell; InsP3R is excluded from the cilia.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…4F), suggesting that decreased vascular stiffening may be an additional factor in reducing systemic vascular resistance in the SS-Plekha7 mutant rat (37). Multiple other BP mediators have effects on vascular remodeling that may contribute to hypertension [e.g., AngII (38) and ET-1 (39)], suggesting that the Plekha7-mediated BP effects are not mechanistically unique, but rather one of the few known genetic risk factors to date that contribute to hypertension risk by affecting vascular function and remodeling. Future studies using an endothelial-specific knockout of Plekha7 will be necessary to demonstrate whether it mediates hypertension risk solely through the vascular endothelium or has other nonendothelial roles in BP regulation.…”

Section: Discussionmentioning

confidence: 99%

Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat

Endres

Priestley²,

Palygin³

et al. 2014

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

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PLEKHA7 (pleckstrin homology domain containing family A member 7) has been found in multiple studies as a candidate gene for human hypertension, yet functional data supporting this association are lacking. We investigated the contribution of this gene to the pathogenesis of salt-sensitive hypertension by mutating Plekha7 in the Dahl salt-sensitive (SS/JrHsdMcwi) rat using zincfinger nuclease technology. After four weeks on an 8% NaCl diet, homozygous mutant rats had lower mean arterial (149 ± 9 mmHg vs. 178 ± 7 mmHg; P < 0.05) and systolic (180 ± 7 mmHg vs. 213 ± 8 mmHg; P < 0.05) blood pressure compared with WT littermates. Albumin and protein excretion rates were also significantly lower in mutant rats, demonstrating a renoprotective effect of the mutation. Total peripheral resistance and perivascular fibrosis in the heart and kidney were significantly reduced in Plekha7 mutant animals, suggesting a potential role of the vasculature in the attenuation of hypertension. Indeed, both flow-mediated dilation and endothelium-dependent vasodilation in response to acetylcholine were improved in isolated mesenteric resistance arteries of Plekha7 mutant rats compared with WT. These vascular improvements were correlated with changes in intracellular calcium handling, resulting in increased nitric oxide bioavailability in mutant vessels. Collectively, these data provide the first functional evidence that Plekha7 may contribute to blood pressure regulation and cardiovascular function through its effects on the vasculature.H ypertension is a complex disease that is characterized by increased blood pressure, renal damage, and vascular dysfunction which collectively increase risk of atherosclerosis, stroke, heart disease, and renal failure in one-quarter of all adults worldwide (1-3). Because there is strong evidence of heritability in hypertension (2, 4, 5), considerable effort has been put toward identifying novel candidate genes and their molecular mechanisms. Genome-wide association studies (GWAS) have identified many potential hypertension loci, which shed light on the genetic complexity of this disease (5-8) but have provided little mechanistic insight. As such, validation and elucidation of the functional roles and disease mechanisms for these gene candidates are the next important challenges (4).Because hypertension is a complex disease (i.e., multiple variants of small effect sizes contributing to disease risk), we hypothesized candidate gene targeting on a genetically sensitized background would reveal functional role(s) of genetic disease modifiers. The Dahl salt-sensitive (SS) rat is an inbred genetic model of salt-sensitive hypertension that displays hypertensioninduced renal damage, cardiac hypertrophy and vascular dysfunction (9-11). These phenotypes are induced by exposing SS rats to a high-salt diet, which results in rapid induction of hypertensive phenotypes that closely resemble salt-induced hypertension seen in humans (12-15). Knockout of specific genes in this disease model using zinc-finger nuclease (ZFN...

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“…Many signaling pathways control ADPKD cyst formation such as the mammalian target of rapamycin (mTOR) [56,57], cyclic adenosine monophosphate (cAMP) [58,59], Wnt signaling pathway [44,60], G protein coupled receptor [GPCR] [61] and Signal Transducer and Activator of Transcription (STAT) signaling pathway [62] (Figure 1).…”

Section: Signaling Pathways As Targets In Pkd Treatmentmentioning

confidence: 99%

Present Status and Advances in Autosomal Dominant Polycystic Kidney Disease

Li¹

2017

Cell Mol Med

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder of the kidney. The mainly clinical manifestation is progressive cyst formation in bilateral kidneys, impairs normal renal parenchyma, and ultimately results in end-stage renal disease (ESRD). Extra-renal lesions include cystic liver or pancreas, brain aneurysm and cardiovascular defects. Mutations in either PKD1 or PKD2 genes result in the disease, but the former develops more severe clinical phenotypes than the latter. Currently, ADPKD still challenge vast clinicians on account of lacking effective and less side-effect therapy. Intensive study of molecular mechanism of the disease can establish theoretical basis for potential therapeutic targets and guide clinicians to develop new approaches in treatment of this disease. This review will focus on current advances of ADPKD pathogenesis which may benefit the translational therapy and precision medicine for the disease treatment. liver failure [25,26]. The prevalence of intracranial aneurysms (ICA) among ADPKD patients is about 12% [27]. A family history of intracranial hemorrhage can significantly increase the risk of ICA [28]. Therefore, examination and evaluation of extrarenal organ of ADPKD patients is also very important.At present, there is no safe and effective treatment of ADPKD in clinic. Therefore, understanding the pathogenesis of ADPKD may provide a new therapeutic target for the clinical treatment and lay the foundation for the development of various biological and drug treatments for ADPKD. [30,31]. Polycystin-1 is found in most segments of the nephron and is distributed in a variety of subcellular structures such as the primary cilia, cytoplasmic vesicles, plasma membrane at focal adhesions, desmosomes, adherens junctions, and possibly endoplasmic reticulum and nuclei. Among them, polycystin-1 distributed in primary cilia is considered to play an important role in the mechano/chemo-sensor function [32][33][34], whereas polycystin-1 distributed in the side wall and the basal body participates in the formation of intercellular adhesion and focal adhesion [35]. In addition, a cleavage product of polycystin-1 that includes the C-terminal tail can translocate to the nucleus and regulate gene transcription [36,37]. PKD Genes and Proteins

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Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Cited by 239 publications

References 164 publications

Cyst formation following disruption of intracellular calcium signaling

Cyst formation following disruption of intracellular calcium signaling

Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat

Present Status and Advances in Autosomal Dominant Polycystic Kidney Disease

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