Regulation of cAMP production in initial and terminal inner medullary collecting ducts

Yasuda, Gen; Jeffries, William B.

doi:10.1046/j.1523-1755.1998.00990.x

Cited by 32 publications

(26 citation statements)

References 27 publications

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“…We previously hypothesized (33) that cysts are formed due to a genetic defect, leading to disturbance of medullary architecture and consequently to an impaired urine concentrating capacity early in the disease when kidney function is still normal. As compensatory mechanism AVP levels increase to maintain fluid balance, AVP in turn causes increased levels of cAMP in collecting tube cells (34), leading to proliferation of tubular cells and chloride-driven fluid secretion into cysts (5,35). Thus, a vicious circle may arise leading to further cyst formation, cyst growth and kidney function decline.…”

Section: Discussionmentioning

confidence: 99%

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

Zittema¹,

Boertien²,

Beek

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease, characterized by cyst formation in the kidneys leading to end stage kidney failure. It is clinically acknowledged that ADPKD patients have impaired urine concentrating capacity, but the mechanism behind this observation is unknown.Design, setting, participants, & measurements Fifteen ADPKD patients (estimated GFR $60 ml/min per 1.73 m 2 ) and 15 age-and sex-matched healthy controls underwent a standard prolonged water deprivation test in which urine and plasma osmolality, vasopressin, and copeptin were measured. The effect of a synthetic vasopressin analog (desmopressin) injected at the moment of maximal urine concentrating capacity was also studied.Results After 14 hours of water deprivation, ADPKD patients tended to have higher plasma osmolality (P=0.07) and significantly higher vasopressin and copeptin levels (both P,0.05), whereas urine osmolality was similar in ADPKD patients and controls (710 versus 742 mOsmol/kg; P=0.61). Maximal urine concentrating capacity was lower in ADPKD patients (758 versus 915 mOsmol/kg in controls; P,0.001). At maximal urine concentrating capacity, plasma osmolality, vasopressin, and copeptin levels were significantly higher in ADPKD patients. The median increase in urine osmolality after desmopressin administration in ADPKD patients was less than in healthy controls.Conclusions Already early in their disease, ADPKD patients have impaired maximal urine concentrating capacity brought out upon dehydration, with no evidence of impaired hypothalamic response. To maintain fluid balance, vasopressin concentration increases, which is hypothesized to play a role in ADPKD disease progression.

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Section: Discussionmentioning

confidence: 99%

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

Zittema¹,

Boertien²,

Beek

et al. 2012

Clinical Journal of the American Society of Nephrology

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“…128 Nearly exclusive localization of V2 receptor (V2R) on collecting ducts, connecting tubules, and thick ascending limbs of Henle, 129,130 the main sites of cystogenesis, 131 minimizes offtarget size effects and improves tolerability. Vasopressin is continuously present in the circulation, likely at a higher level in PKD to compensate for a urinary concentrating defect.…”

Section: V2 Receptor Antagonists: Rationale and Preclinical Trialsmentioning

confidence: 99%

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

244

218

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Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling.

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“…14,15 PDE1 accounts for most of the PDE activity in renal tubules 16,17 and is the only PDE activated by calcium 14,15 (which is reduced in PKD cells), and its activity is reduced in cystic kidneys. 17 Furthermore, the pool of cAMP generated in response to vasopressin (the main adenylyl cyclase agonist in collecting duct and distal nephron 18 ) is mainly hydrolyzed by PDE1, and the accumulation of cAMP in response to vasopressin is markedly increased when intracellular calcium is reduced, mainly because of lower PDE1 activity. 19,20 PDE3 is inhibited by cGMP 21 (which is degraded by PDE1), localizes to ER membranes, 22 and hydrolyzes cAMP pools that control two major factors in the pathogenesis of PKD: tubular epithelial cell proliferation 23,24 and cystic fibrosis transmembrane conductance regulator (CFTR) -driven chloride secretion.…”

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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Regulation of cAMP production in initial and terminal inner medullary collecting ducts

Cited by 32 publications

References 27 publications

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

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

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