Vasopressin and disruption of calcium signalling in polycystic kidney disease

Chebib, Fouad T.; Sussman, Caroline R.; Wang, Xiaofang; Harris, Peter C.; Torres, Vicente E.

doi:10.1038/nrneph.2015.39

Cited by 108 publications

(104 citation statements)

References 190 publications

(174 reference statements)

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“…PC2 is a nonselective cation channel with high permeability for calcium. 2 Both PCs interact with several calcium channel and sensor proteins. Substantial experimental evidence supports the hypothesis that disruption of intracellular calcium homeostasis and upregulation of the cAMP signaling have a central role in the pathogenesis of PKD.…”

Section: /Ws25mentioning

confidence: 99%

Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies

Wang

Sussman

et al. 2015

JASN

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Aberrant intracellular calcium levels and increased cAMP signaling contribute to the development of polycystic kidney disease (PKD). cAMP can be hydrolyzed by various phosphodiesterases (PDEs). To examine the role of cAMP hydrolysis and the most relevant PDEs in the pathogenesis of PKD, we examined cyst development in Pde1-or Pde3-knockout mice on the Pkd2 2/WS25 background (WS25 is an unstable Pkd2 allele). These PDEs were selected because of their importance in cross-talk between calcium and cyclic nucleotide signaling (PDE1), control of cell proliferation and cystic fibrosis transmembrane conductance regulator (CFTR) -driven fluid secretion (PDE3), and response to vasopressin V2 receptor activation (both). In Pkd2 2/WS25mice, knockout of Pde1a, Pde1c, or Pde3a but not of Pde1b or Pde3b aggravated the development of PKD and was associated with higher levels of protein kinase Aphosphorylated (Ser133) cAMP-responsive binding protein (P-CREB), activating transcription factor-1, and CREB-induced CRE modulator proteins in kidney nuclear preparations. Immunostaining also revealed higher expression of P-CREB in Pkd2 2/WS25 ;Pde1a 2/2 , Pkd2 2/WS25 ;Pde1c 2/2 , and Pkd2 2/WS25 ;Pde3a 2/2 kidneys.The cystogenic effect of desmopressin administration was markedly enhanced in Pkd2 2/WS25 ;Pde3a 2/2 mice, despite PDE3 accounting for only a small fraction of renal cAMP PDE activity. These observations show that calcium-and calmodulindependent PDEs (PDE1A and PDE1C) and PDE3A modulate the development of PKD, possibly through the regulation of compartmentalized cAMP pools that control cell proliferation and CFTR-driven fluid secretion. Treatments capable of increasing the expression or activity of these PDEs may, therefore, retard the development of PKD.

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Section: /Ws25mentioning

confidence: 99%

Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies

Wang

Sussman

et al. 2015

JASN

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“…replacement therapy which includes dialysis and transplantation [6]. The PCK rat represents a reliable experimental model of PKD that has been widely used to evaluate the efficacy of pharmacological interventions designed to ameliorate PKD.…”

Section: Discussionmentioning

confidence: 99%

High Resolution Ultrasonography for Assessment of Renal Cysts in the PCK Rat Model of Autosomal Recessive Polycystic Kidney Disease

Kapoor¹,

Rodríguez²,

Mitchell

et al. 2016

Kidney Blood Press Res

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Background/Aims: The PCK rat model of polycystic kidney disease is characterized by the progressive development of renal medullary cysts. Here, we evaluated the suitability of high resolution ultrasonography (HRU) to assess the kidney and cyst volume in PCK rats, testing three different ultrasound image analysis methods, and correlating them with kidneys weights and histological examinations. Methods: After inducing anesthesia, PCK rats (n=18) were subjected to HRU to visualize the kidneys, to perform numeric and volumetric measurements of the kidney and any cysts observed, and to generate 3-dimensional images of the cysts within the kidney parenchyma. Results: HRU provided superior information in comparison to microscopic analysis of stained kidney sections. HRU-based kidney volumes correlated strongly with kidney weights (R²=0.809; P<0.0001). Conclusion: HRU represents a useful diagnostic tool for kidney and cyst volume measurements in PCK rats. Sequential HRU examinations may be useful to study the effect of drugs on cyst growth without the need to euthanize experimental animals.

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“…Elevated intracellular cAMP plays a pivotal role in the cellular processes that lead to the development of a PKD phenotype [13]. Accordingly, renal cAMP levels are elevated in PCK rats compared to wild-type animals, and a positive correlation exists between the tissue levels of cAMP and the severity of PKD [3].…”

Section: Effect On Markers Of Renal Functionmentioning

confidence: 99%

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

Wang¹,

Constans²,

Chebib³

et al. 2019

Am J Nephrol

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Background: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. Methods: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3′,5′-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. Results: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. Conclusions: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

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Vasopressin and disruption of calcium signalling in polycystic kidney disease

Cited by 108 publications

References 190 publications

Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies

Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies

High Resolution Ultrasonography for Assessment of Renal Cysts in the PCK Rat Model of Autosomal Recessive Polycystic Kidney Disease

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

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