Antidiuretic hormone resistance in the neonatal cortical collecting tubule is mediated in part by elevated phosphodiesterase activity

Quigley, Raymond; Chakravarty, Sumana; Baum, Michel

doi:10.1152/ajprenal.00122.2003

Cited by 32 publications

(18 citation statements)

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“…Therefore, it had been assumed that increased phosphodiesterase activity was not a significant factor limiting the response of the CD to AVP. Recently, Quigley et al (86) confirmed previous observations of elevated intracellular levels of phosphodiesterase in neonatal CCD. Furthermore, they were able to show that rolipram, a specific inhibitor of phosphodiesterase IV, not only decreased phosphodiesterase activity in the immature CCD to adult levels but, more significantly, abolished the blunted AVP-stimulated osmotic water permeability in isolated, microperfused immature CCD (86).…”

Section: Role Of Phosphodiesterasessupporting

confidence: 54%

Development of water transport in the collecting duct

Bonilla–Félix¹

2004

American Journal of Physiology-Renal Physiology

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Bonilla-Felix, Melvin. Development of water transport in the collecting duct. Am J Physiol Renal Physiol 287: F1093-F1101, 2004; doi:10.1152/ajprenal.00119. 2004.-The ability of the immature kidney to concentrate urine is lower than in adults. This can lead to severe water and electrolyte disorders, especially in premature babies. Resistance to AVP and lower tonicity of the medullary interstitium seem to be the major factors limiting urine concentration in newborns. AVP-stimulated cAMP generation is impaired. This is the result of inhibition of the production by PGE 2 acting through EP3 receptors and increased degradation by phosphodiesterase IV. The expression of aquaporin-2 (AQP2) in the immature kidney is low; however, under conditions of water deprivation and after stimulation with DDAVP, it rises to adult levels. The expression of AQP3 and AQP4 is intact at birth and does not seem to contribute to the hyporesponsiveness to AVP. Low sodium transport by thick ascending loops of Henle, immaturity of the medullary architecture, and adaptations in the transport of urea contribute to the lower tonicity of the medullary interstitium. This paper reviews the alterations in the AVP signal transduction pathway in the immature kidney. immature kidney; arginine vasopressin; aquaporins; prostaglandins WATER CONSERVATION IS ONE of the most important functions of the kidney. Before birth, the ability of the organism to conserve water is not critical as the placenta controls fluid balance in the fetus. The event of birth prompts abrupt changes in the infant's environment, rendering the newborn responsible for keeping fluid and electrolyte homeostasis. Although nephrogenesis in full-term human infants is completed before birth, tubular development continues during the first few years of life. This limits the ability of the immature kidney to reabsorb water, which usually reaches adult levels by 1 yr of age. As early as 1941, McCance and Young (72) observed that the urine of a group of infants from 7 to 14 days of age was always hypotonic (72). Studies in young rats (first 3 wk of life) subjected to 8 h of dehydration showed that the maximal osmolality achieved was close to 1,000 mosmol/kgH 2 O, which was only ϳ50% of the levels reached by adult rats subjected to the same stimulus (32).In infants, total body water is higher at birth (45, 91). Under normal physiological conditions, the kidneys have to excrete this load of water during the first week of life (91). Therefore, maximal abilities to concentrate urine are not considered necessary at birth. However, this limitation places premature infants, who frequently have other associated medical problems, at greater risk for serious imbalances in water and electrolyte homeostasis (20,101,104). For years, scientists have tried to identify the factors mediating the limitation in urine concentration observed in the immature kidney. The major aim of this paper is to review the progress in investigating the development of water transport in the collecting duct (CD) and its respons...

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Section: Role Of Phosphodiesterasessupporting

confidence: 54%

Development of water transport in the collecting duct

Bonilla–Félix¹

2004

American Journal of Physiology-Renal Physiology

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Section: Development Of Urinary Concentration and Dilutionmentioning

confidence: 62%

“…Neonatal CT water permeability did not increase in response to vasopressin to the same extent as that seen in the adult [312][313][314][315]. Studies have shown that the phosphodiesterase activity is greater in the neonatal collecting tubule [313]. The water permeability of the neonatal collecting tubule was identical to the adult in the presence of a phosphodiesterase inhibitor demonstrating that the predominant factor limiting the action of vasopressin in the collecting tubule was the enhanced degradation of cAMP generated by vasopressin in the neonatal collecting tubule [313].…”

Section: Development Of Urinary Concentration and Dilutionmentioning

confidence: 74%

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Renal Tubular Development

Baum

2014

Pediatric Nephrology

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The nephron is faced with the enormous task of maintaining a constant composition and volume of the extracellular fluid. The amount of electrolytes and water ingested and absorbed must be eliminated, and the waste products from metabolism must also be excreted. This challenge is all the more complex as our dietary intake is quite variable from day to day. Despite this variable intake, there is virtually no change in the volume or composition of the extracellular fluid volume from day to day.There are two possible ways that our kidney could balance ingestion and excretion. The kidney could be a secretory organ where all the excess solutes and water ingested would be excreted by tubular secretion. This would be very inefficient and require an enormous amount of energy. In addition, in times of a disturbance in the extracellular fluid volume such as a high salt intake or volume loss from diarrhea, the regulatory systems necessary to maintain a constant extracellular fluid volume and composition while excreting waste products would be very complex. On the other hand, the kidney could filter an enormous quantity of extracellular fluid, which would be very efficient in removing waste products, and reclaim the desired salt, organic solutes, and water. With volume depletion, a greater fraction of salt and water could be reabsorbed, and when one has a dietary indiscretion such as the salt intake from a pepperoni pizza, there could be a reduction in sodium reabsorption leading to an increase in excretion to bring us back into balance. The mammalian kidney actually uses both mechanisms to perform its job which is necessary for our survival on land. The adult kidney filters~150 l of isotonic fluid a day and reclaims most of it, leaving the waste produces to be excreted in about 1.5 l of urine. In addition, there are secretory processes for solutes such as organic anions and cations in the proximal tubule and secretory mechanisms to excrete the excess acid generated from metabolism in the distal nephron which aid in maintaining homeostasis.To accomplish the remarkable task of reclamation of the necessary solutes and water to maintain a constant composition of the extracellular fluid volume, the mammalian kidney has evolved into a highly specialized organ with thousands of units called nephrons. Each human kidney has approximately one million nephrons. Each nephron is a tube consisting of epithelial cells and is divided into 12 specialized segments as shown in Fig. 1. The epithelial cells allow for the vectorial transport of solutes. The proximal tubule is responsible for the bulk reclamation of solutes and water and for the secretion of organic cations and anions. Approximately two-thirds of the glomerular filtrate is reabsorbed by the proximal tubule in an isotonic fashion. Virtually all of the organic solutes, as well as the majority of bicarbonate, phosphate, and chloride, are reabsorbed in this segment. The proximal tubule is divided into S 1 , S 2 , and S 3 segments based on the rates of transport of some solutes and mor...

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“…Evidence suggests that ␤-adrenergic signaling promotes Na excretion by facilitating a blood-lumen flux of Na ϩ , 20 whereas other studies have indicated that ␤-adrenergic signaling inhibits Na ϩ uptake in tubules by stimulating basolateral Na/K ATPase. [22][23][24] Additional renal effects of rolipram that have been reported include regulation of the osmotic permeability response to antidiuretic hormone in neonatal tubules 25 and renin release from juxtaglomerular cells. 26 Both the Dahl SS rats and SHRs are generally considered to be models of renal hypertension.…”

Section: Discussionmentioning

confidence: 99%

Renal Phosphodiesterase 4B Is Activated in the Dahl Salt-Sensitive Rat

et al. 2008

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Abstract-Reduced ␤-adrenoreceptor signaling is associated with increased sympathoadrenal activity in hypertensive patients and animal models of hypertension. However, the mechanism that accounts for this characteristic decline in ␤-adrenergic signaling is unclear. In the present study, we investigated renal phosphodiesterase 4B, which metabolizes cAMP. Immunoblot analysis detected only the phosphodiesterase 4B4 isoform present in kidney tissue from spontaneously hypertensive rats, hypertensive Dahl salt-sensitive (SS) rats, and Dahl salt-resistant rats. The phosphorylated (activated) form of the protein was present at 2-fold greater levels in Dahl SS rats than in spontaneously hypertensive rats and Dahl salt-resistant rats, whereas the unphosphorylated form of the protein was reduced by approximately one half in SS animals. In accord with immunoblot data, rolipram-inhibitable cAMP hydrolyzing activity, a measure of PDE4 activity, was Ϸ3-fold greater in kidney cytosolic extracts from SS rats than in extracts from spontaneously hypertensive rats and salt-resistant rats. Phosphodiesterase 4B expression was detected by immunohistochemistry in the renal vasculature, proximal tubules, and distal tubules. These results raise the possibility that increased PDE4 activity, specifically phosphodiesterase 4B4 activity, reduces ␤-adrenergic signaling in the kidney and contributes to salt-sensitive hypertension in the Dahl SS rat. Key Words: phosphodiesterase 4B Ⅲ cAMP Ⅲ Dahl rat Ⅲ ␤-adrenergic signaling A ctivation of ␤-adrenoreceptors triggers the formation of cAMP through G protein-coupled adenylate cyclase, which subsequently stimulates cAMP-dependent protein kinase A (PKA). cAMP phosphodiesterase (PDE) negatively regulates ␤-adrenoreceptor signaling by hydrolyzing cAMP and reducing PKA activity. 1,2 Reduced vascular ␤-adrenergic responsiveness has been demonstrated in both hypertensive patients and rat models of genetic and acquired hypertension (see review 3 ). This reduced responsiveness has been hypothesized to play an important role in the pathogenesis of hypertension. However, the mechanism(s) underlying reduced ␤-adrenergic signaling remain unclear. ␤-Adrenergic receptor number has been measured in different animal hypertension models, and the results have varied, with receptor number increasing, decreasing, or remaining unchanged in the heart and vasculature (see review 4 ). Other evidence suggests that, in certain models of hypertension, expression of the stimulatory G protein Gs is reduced, and/or the expression of the inhibitory G protein Gi is increased. [5][6][7] Another possibility, which we have investigated here, is that PDE activity may be increased in hypertension.The PDE 4 family of PDEs, formerly known as cAMP-PDE and rolipram-sensitive PDE, is expressed in most cell types and is generally considered to account for most of the cAMP-hydrolyzing activity of cells (see review 8 ). PDE4s are generated from 4 distinct genes (PDE4A through D), and each gene generates long and short splice variants using alte...

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Antidiuretic hormone resistance in the neonatal cortical collecting tubule is mediated in part by elevated phosphodiesterase activity

Cited by 32 publications

References 40 publications

Development of water transport in the collecting duct

Development of water transport in the collecting duct

Renal Tubular Development

Renal Phosphodiesterase 4B Is Activated in the Dahl Salt-Sensitive Rat

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