Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies done in cell culture have demonstrated that insulin activates the epithelial sodium channel (ENaC) via a variety of mechanisms. However, to date, upregulation of ENaC in native renal tissue by in vivo administration of insulin has not been demonstrated. To address this, we injected 6-mo-old male C57BL/CBA mice (n = 14/group) intraperitoneally with vehicle or 0.5 U/kg body wt insulin and examined short-term (1-2 h) sodium excretion and kidney ENaC subunits (alpha, beta, and gamma) and serum and glucocorticoid-induced kinase (SGK-1) regulation. Insulin resulted in a significant reduction in urine sodium (by approximately 80%) that was restored by intraperitoneal administration of the ENaC antagonist, benzamil (1.4 mg/kg body wt). Differential centrifugation followed by Western blotting of whole kidney revealed significantly increased band densities (by 26-103%) for insulin- relative to vehicle-treated mice for alpha- and gamma-ENaC in the homogenate (H), and plasma membrane-enriched fraction (MF), with no difference in the vesicle-enriched fraction (VF). Similarly, beta-ENaC was significantly increased in MF (by 45%) but no change in the H. It was, however, significantly decreased in the VF (by 28%) with insulin. In agreement, immunoperoxidase labeling demonstrated relatively stronger apical, relative to cytosolic, localization of alpha-, beta-, and gamma-ENaC with insulin, whereas, with vehicle, labeling was fairly evenly dispersed throughout collecting duct principal cells. Furthermore, Western blotting showed insulin increased SGK-1 (by 75%) and phosphorylated-SGK band densities (by 30%) but only in the MF. These studies demonstrate novel in vivo regulation of renal ENaC activity and subunit proteins and SGK-1 by insulin in the acute time frame in the mouse.
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PMID:Trafficking of ENaC subunits in response to acute insulin in mouse kidney. 1738 77

Thiazolidinediones (TZDs) or glitazones are agents that are widely used for the treatment of type 2 diabetes mellitus. These drugs have a multitude of therapeutic effects including reduction in insulin resistance and hyperglycaemia, anti-inflammatory effects and amelioration of hypertension, microalbuminuria and hepatic steatosis. The TZD molecular target, peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear transcription factor, is expressed diffusely in humans, including many tissues comprising the cardiovascular and renal systems. This suggests a potential for TZDs to elicit perturbing effects on these systems, which are independent of their effects on glucose and lipid metabolism. One of the most common adverse effects of TZDs is fluid retention, which can result in, or exacerbate, oedema and congestive heart failure (CHF). The frequency of peripheral oedema is approximately 5% when TZDs are used in mono- or combination oral therapy, and about 15% when used with insulin. Patients with type 2 diabetes are at high risk of myriad morbid complications, including CHF. The development of CHF, particularly in the elderly, is a harbinger of premature mortality. TZD-induced oedema is largely peripheral, may have its origins in changes in haemodynamics, with some contribution from molecules, which regulate cell and tissue permeability (e.g. vascular endothelial growth factor and protein kinase Cbeta), and remains the preponderant manifestation of TZD-induced fluid retention even in those with existing heart failure. Preclinical and pilot clinical data attest to the fact that at least part of the fluid retention derives from a direct effect of TZDs on sodium reabsorption via the renal medullary collecting duct, a mechanism that is sensitive to diuretic agents that have this nephron segment as their site of action, in whole or in part (spironolactone, amiloride and hydrochlorothiazide). Our review suggests various potential clinical strategies by which TZD-induced fluid retention might be effectively monitored and addressed.
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PMID:Thiazolidinediones and their fluid-related adverse effects: facts, fiction and putative management strategies. 1772 67

Thiazolidinediones (TZDs) are relatively new agents for the treatment of type 2 diabetes. They act as agonists at the PPAR-gamma nuclear receptor and their therapeutic effects include decreased insulin resistance and hyperglycaemia, an improved plasma lipid, inflammation and pro-coagulant profile, and amelioration of hypertension, microalbuminuria and hepatic steatosis. The most common side effects of TZDs include weight gain and oedema, with occasional reports of congestive heart failure (CHF). This review discusses the benefit-risk profile of TZDs in treating patients with type 2 diabetes, with particular reference to the heart. To provide context, we explore briefly the epidemiology and pathophysiology of heart failure in patients with type 2 diabetes, touch on the association of heart disease and cardiovascular mortality with antihyperglycaemic treatment modalities other than TZDs, and then focus on the effects of TZDs on the heart, cardiovascular risk factors and outcomes. We describe the cluster of host factors, which seems to predispose patients with type 2 diabetes to TZD-induced or TZD-exacerbated oedema and CHF and then provide an overview of the putative mechanisms of these TZD-related side effects. We also propose that certain diuretics (amiloride and spironolactone), by targeting the distal nephron that expresses PPARgamma in collecting duct cells, might be of benefit in ameliorating the fluid retention and oedema associated with TZDs.
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PMID:Thiazolidinedione insulin sensitizers and the heart: a tale of two organs? 1833 90

Renal tubule epithelial cells express the insulin receptor (IR); however, their value has not been firmly established. We generated mice with renal epithelial cell-specific knockout of the IR by Cre-recombinase-loxP recombination using a kidney-specific (Ksp) cadherin promoter. KO mice expressed significantly lower levels of IR mRNA and protein in kidney cortex (49-56% of the WT) and medulla (32-47%) homogenates. Immunofluorescence showed the greatest relative reduction in the thick ascending limb and collecting duct cell types. Body weight, kidney weight, and food and water intakes were not different from WT littermates. However, KO mice had significantly increased basal systolic blood pressure (BP, 15 mm Hg higher) as measured by radiotelemetry. In response to a volume load by gavage (20 ml/kg of body weight, 0.9% NaCl, 15% dextrose), KO mice had impaired natriuresis (37 +/- 10 versus 99 +/- 9 mmol of Na(+) per 2 h in WT). Furthermore, volume load led to a sustained increase in BP in KO mice only. In contrast, insulin administration i.p. (0.5 units/kg of body weight) resulted in a significant fall in BP in WT, but not in KO mice. To test the role of reduced renal nitric oxide (NO) production in these responses, basal urinary nitrates plus nitrites excretion (UNOx) was measured and found to be 61% lower in KO vs. WT mice. Furthermore, acute insulin increased UNOx by 202% in the WT, relative to a significantly blunted rise (67%) in KO animals. These results illuminate a previously uncharacterized role for renal IR to reduce BP and facilitate sodium and water excretion, possibly via NO production.
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PMID:Impaired sodium excretion and increased blood pressure in mice with targeted deletion of renal epithelial insulin receptor. 1842 59

The pathways implicated in the control of epithelial Na(+) channel (ENaC)-dependent Na(+) transport in renal collecting duct cells share substantial parallels with those implicated in insulin-regulated glucose metabolism. Notably, both are inhibited by wortmannin and LY294002 and signal through phosphatidylinositol-3-kinase (PI3K)-dependent kinases SGK1 and Akt. The inhibitor pattern is thought to reflect dependence on PI3K activity since wortmannin and LY294002 are both effective inhibitors of this kinase. However, these inhibitors block a variety of kinases from different families and lack specificity within the PI3K family. To begin to dissect more precisely the pathways required for signaling and for control of Na(+) transport in renal collecting duct cells, we have examined the effect of a set of PI3K inhibitors, which selectively block distinct subsets of PI3K catalytic subunit isoforms. We have found that ENaC-dependent Na(+) transport was blocked by inhibitors of the p110-alpha isoform of PI3K, but not by inhibitors of p110-beta, -gamma, or -delta. Inhibitors that block Na(+) current also blocked SGK1 and Akt phosphorylation. In contrast to insulin-stimulated glucose uptake in muscle cells, p110-beta inhibition did not enhance sensitivity to p110-alpha inhibition. These data support the conclusion that ENaC-dependent Na(+) current is controlled exclusively by p110-alpha, the same isoform that is the principal mediator of insulin effects on glucose metabolism, and lacks any dependence on p110-beta. These findings further underscore the extent to which Na(+) and glucose regulation are intertwined and provide additional insight into the interconnections between diabetes and hypertension.
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PMID:Activity of the p110-alpha subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport. 1865 76

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor subtype gamma (PPARgamma) activators that are clinically used as an insulin sensitizer for glycemic control in patients with type 2 diabetes. Additionally, TZDs exhibit novel anti-inflammatory, antioxidant, and antiproliferative properties, indicating therapeutic potential for a wide variety of diseases associated with diabetes and other conditions. The clinical applications of TZDs are limited by the common major side effect of fluid retention. A better understanding of the molecular mechanism of TZD-induced fluid retention is essential for the development of novel therapies with improved safety profiles. An important breakthrough in the field is the finding that the renal collecting duct is a major site for increased fluid reabsorption in response to rosiglitazone or pioglitazone. New evidence also indicates that increased vascular permeability in adipose tissues may contribute to edema formation and body weight gain. Future research should therefore be directed at achieving a better understanding of the detailed mechanisms of TZD-induced increases in renal sodium transport and in vascular permeability.
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PMID:Renal and vascular mechanisms of thiazolidinedione-induced fluid retention. 1878 48

The renal cortico-papillary osmotic gradient is generated by sodium reabsorption in the thick ascending limb. The antidiuretic hormone arginine vasopressin (AVP) increases collecting duct water permeability by enhancing aquaporin-2 (AQP2) water channel insertion in the apical membrane of principal cells, allowing water to passively flow along the osmotic gradient from the tubule lumen to the interstitium. In addition to short-term AQP2 redistribution between intracellular compartments and the cell surface, AQP2 whole cell abundance is tightly regulated. AVP is a major transcriptional activator of the AQP2 gene, and stimulation of insulin- and calcium-sensing receptors respectively potentiate and reduce its action. Extracellular tonicity is another key factor that determines the levels of AQP2 abundance. Its effect is dependent on activation of the tonicity-responsive enhancer binding protein that reinforces AVP-induced AQP2 transcriptional activation. Conversely, activation of the NF-kappaB transcriptional factor by proinflammatory factors reduces AQP2 gene transcription. Aldosterone additionally regulates AQP2 whole cell abundance by simultaneously reducing AQP2 gene transcription and stimulating AQP2 mRNA translation. These examples illustrate how cross talk between various stimuli regulates AQP2 abundance in collecting duct principal cells and consequently contributes to maintenance of body water homeostasis.
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PMID:Aquaporin-2 abundance in the renal collecting duct: new insights from cultured cell models. 1924 7

The aldosterone-sensitive distal nephron (ASDN) includes the late distal convoluted tubule 2, the connecting tubule (CNT) and the collecting duct. The appropriate regulation of sodium (Na(+)) absorption in the ASDN is essential to precisely match urinary Na(+) excretion to dietary Na(+) intake whilst taking extra-renal Na(+) losses into account. There is increasing evidence that Na(+) transport in the CNT is of particular importance for the maintenance of body Na(+) balance and for the long-term control of extra-cellular fluid volume and arterial blood pressure. Na(+) transport in the CNT critically depends on the activity and abundance of the amiloride-sensitive epithelial sodium channel (ENaC) in the luminal membrane of the CNT cells. As a rate-limiting step for transepithelial Na(+) transport, ENaC is the main target of hormones (e.g. aldosterone, angiotensin II, vasopressin and insulin/insulin-like growth factor 1) to adjust transepithelial Na(+) transport in this tubular segment. In this review, we highlight the structural and functional properties of the CNT that contribute to the high Na(+) transport capacity of this segment. Moreover, we discuss some aspects of the complex pathways and molecular mechanisms involved in ENaC regulation by hormones, kinases, proteases and associated proteins that control its function. Whilst cultured cells and heterologous expression systems have greatly advanced our knowledge about some of these regulatory mechanisms, future studies will have to determine the relative importance of the various pathways in the native tubule and in particular in the CNT.
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PMID:Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC). 1927 1

Hyperfiltration occurs in early type 1 diabetes mellitus in both rats and humans. It results from afferent vasodilation and thus may impair stabilization of glomerular capillary pressure by autoregulation. It is inversely related to dietary salt intake, the "salt paradox." Restoration of normal glomerular filtration rate (GFR) involves increased preglomerular resistance, probably mediated by tubuloglomerular feedback (TGF). To begin to test whether the salt paradox has pathogenic significance, we compared intact vs. diabetic (streptozotocin) Long-Evans rats with normal and increased salt intake, 1 and approximately 3% by weight of food eaten, respectively. Weekly 24-h blood pressure records were acquired by telemetry before and during diabetes. Blood glucose was maintained at approximately 20 mmol/l by insulin implants. GFR was significantly elevated only in diabetic rats on normal salt intake, confirming diabetic hyperfiltration and the salt paradox. Renal blood flow dynamics show strong contributions to autoregulation by both TGF and the myogenic mechanism and were not impaired by diabetes or by increased salt intake. Separately, systolic pressure was not elevated in diabetic rats at any time during 12 wk with normal or high salt intake. Autoregulation was effective in all groups, and the diabetic-normal salt group showed significantly improved autoregulation at low perfusion pressures. Histological examination revealed very minor glomerulosclerosis and modest mesangial expansion, although neither was diagnostic of diabetes. Periodic acid-Schiff-positive droplets found in distal tubules and collecting duct segments were diagnostic of diabetic kidneys. Biologically significant effects attributable to increased salt intake were abrogation of hyperfiltration and of the left shift in autoregulation in diabetic rats.
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PMID:Salt-resistant blood pressure and salt-sensitive renal autoregulation in chronic streptozotocin diabetes. 1933 76

The epithelial sodium channel (ENaC) is believed to represent the rate-limiting step for sodium absorption in the renal collecting duct. Consequently, ENaC is a central effector affecting systemic blood volume and pressure. Sodium and water transport are dysregulated in diabetes mellitus. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are currently used in the treatment of type 2 diabetes, although their use remains limited by fluid retention. The effects of PPARgamma agonists on ENaC activity remain controversial. Although PPARgamma agonists were shown to stimulate ENaC-mediated renal salt absorption, probably via the serum- and glucocorticoid-regulated kinase 1, other studies reported that the PPARgamma agonist-induced fluid retention is independent of ENaC activity. Here we confirmed that four chemically distinct PPARgamma agonists [pioglitazone, rosiglitazone, troglitazone, and 15-deoxy-Delta12,14-prostaglandin J2 (PGJ2)] do not enhance Na+ transport in cultured renal collecting duct principal mpkCCDc14 cells, as assessed by short-circuit current measurements. However, the PPARgamma antagonist 2-chloro-5-nitro-N-4-pyridinyl-benzamide (T0070907), and to a lesser extent 2-chloro-5-nitrobenzanilide (GW9662), were found to decrease Na+ reabsorption across mpkCCDc14 cell layers. Furthermore, pretreatment of monolayers with T0070907 diminished the insulin-stimulated sodium transport. PPARgamma agonist PGJ2 did not enhance insulin-stimulated Na+ flux via ENaC. We also show that PPARgamma enhances ENaC activity when all three subunits are reconstituted in Chinese hamster ovary (CHO) cells. GW9662 inhibits ENaC activity when ENaC subunits are coexpressed in CHO cells with PPARgamma. In contrast, rosiglitazone has no effect on ENaC activity. We conclude that PPARgamma activity is important for maintaining basal and insulin-dependent transepithelial Na+ transport and ENaC activity.
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PMID:Peroxisome proliferator-activated receptor gamma antagonists decrease Na+ transport via the epithelial Na+ channel. 1975


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