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

Aldosterone controls the activity of the amiloride-sensitive epithelial Na+ channel located in the apical membrane of epithelial cells from the distal colon and kidney collecting duct. This channel is a key element in the antinatriuretic response to aldosterone. It consists of three homologous subunits, alpha-ENaC, beta-ENaC, and gamma-ENaC (for epithelial Na+ channel), which share significant identity with degenerins, a family of proteins found in the nematode Caenorhabditis elegans, and with ligand-gated cation channels, such as FaNaC [Phe-Met-Arg-Phe-NH2 (i.e., FMRF-amide) Na+ channel] or ASIC (acid-sensing ion channel), two neuronal ionotropic receptors for Phe-Met-Arg-Phe-NH2 and H+, respectively. All of these proteins contain a large extracellular loop located between two large hydrophobic domains. The NH2- and COOH-terminal domains are cytoplasmic and contain potential regulatory motifs. Gain-of-function mutations affecting beta-ENaC and gamma-ENaC genes can cause Liddle syndrome, a rare from of genetic hypertension. Loss-of-function mutations affecting alpha-ENaC or beta-ENaC genes can cause pseudohypoaldosteronism type 1. Steroids strongly increase beta-ENaC and gamma-ENaC transcription in rat distal colon. A different situation is observed in rat kidney, in which the large stimulation of ENaC activity is mainly via posttranslational mechanisms. In both tissues, aldosterone increases cell surface expression of the ENaC subunits.
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PMID:Molecular biology of Na+ absorption. 931 61

The epithelial sodium channel (ENaC) plays a major role in the regulation of sodium balance and BP by controlling Na(+) reabsorption along the renal distal tubule and collecting duct (CD). ENaC activity is affected by extracellular nucleotides acting on P2 receptors (P2R); however, there remain uncertainties over the P2R subtype(s) involved, the molecular mechanism(s) responsible, and their physiologic role. This study investigated the relationship between apical P2R and ENaC activity by assessing the effects of P2R agonists on amiloride-sensitive current in the rat CD. Using whole-cell patch clamp of principal cells of split-open CD from Na(+)-restricted rats, in combination with immunohistochemistry and real-time PCR, we found that activation of metabotropic P2R (most likely the P2Y(2) and/or (4) subtype), via phospholipase C, inhibited ENaC activity. In addition, activation of ionotropic P2R (most likely the P2X(4) and/or (4/6) subtype), via phosphatidylinositol-3 kinase, either inhibited or potentiated ENaC activity, depending on the extracellular Na(+) concentration; therefore, it is proposed that P2X(4) and/or (4/6) receptors might function as apical Na(+) sensors responsible for local regulation of ENaC activity in the CD and could thereby help to regulate Na(+) balance and systemic BP.
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PMID:Sodium-dependent regulation of renal amiloride-sensitive currents by apical P2 receptors. 1823 98

Extracellular nucleotides (e.g., ATP) activate ionotropic P2X and metabotropic P2Y receptors in the plasma membrane to regulate and maintain cell function and integrity. This includes the renal tubular and collecting duct system, where the locally released nucleotides act in a paracrine and autocrine way to regulate transport of electrolytes and water and maintain cell volume. A prominent role has been assigned to Gq-coupled P2Y(2) receptors, which are typically activated by both ATP and UTP. Studies in gene knockout mice revealed an antihypertensive activity of P2Y(2) receptors that is linked to vasodilation and an inhibitory influence on renal salt reabsorption. Flow induces apical ATP release in the thick ascending limb, and first evidence indicates an inhibitory influence of P2Y(2) receptor tone on the expression and activity of the Na-K-2Cl cotransporter NKCC2 in this segment. The apical ATP/UTP/P2Y(2) receptor system in the connecting tubule/cortical collecting duct mediates the inhibitory effect of dietary salt on the open probability of the epithelial sodium channel ENaC and inhibits ENaC activity during aldosterone escape. Connexin 30 has been implicated in the luminal release of the ATP involved in the regulation of ENaC. An increase in collecting duct cell volume in response to manipulating water homeostasis increases ATP release. The subsequent activation of P2Y(2) receptors inhibits vasopressin-induced cAMP formation and water reabsorption, which facilitates water excretion and stabilizes cell volume. Thus recent studies have established the ATP/UTP/P2Y(2) receptor system as a relevant regulator of renal salt and water homeostasis and blood pressure regulation. The pathophysiological relevance and therapeutic potential remains to be determined, but dual effects of P2Y(2) receptor activation on both the vasculature and renal salt reabsorption implicate these receptors as potential therapeutic targets in hypertension.
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PMID:Regulation of renal NaCl and water transport by the ATP/UTP/P2Y2 receptor system. 2171 71

Background: Probenecid is a uricosuric agent that in addition to exerting a positive ionotropic effect in the heart, blocks the ATP transporter Pannexin 1 and inhibits the Cl-/HCO3- exchanger, pendrin. In the kidney, pendrin blunts the loss of salt wasting secondary to the inhibition of the thiazide-sensitive Na+-Cl- co-transporter (NCC/SLC12A3). Hypothesis: Pre-treatment with probenecid down-regulates pendrin; therefore, leaving NCC as the main salt absorbing transporter in the distal nephron, and hence enhances the hydrochlorothiazide (HCTZ)-induced diuresis. Methods: Daily balance studies, blood and urine chemical analysis, immunofluorescence, as well as western and northern blot analyses were utilized to examine the effects of probenecid alone (at 250 mg/kg/day) or in combination with HCTZ (at 40 mg/kg/day) on kidney function and on salt and water transporters in the collecting duct. Results: Male Sprague Dawley rats were subjected to three different protocols: (1) HCTZ for 4 days, (2) probenecid for 10 days, and (3) primed with probenecid for 6 days followed by probenecid and HCTZ for 4 additional days. Treatment protocol 1 (HCTZ for 4 days) only mildly increased the urine volume (U Vol) from a baseline of 9.8-13.4 ml/day. In response to treatment protocol 2 (probenecid for 10 days), U Vol increased to 15.9 ml/24 h. Treatment protocol 3 (probenecid for 6 days followed by probenecid and HCTZ for 4 additional days) increased the U Vol to 42.9 ml/day on day 4 of co-treatment with HCTZ and probenecid (compared to probenecid p = 0.003, n = 5 or HCTZ alone p = 0.001, n = 5). Probenecid treatment at 250 mg/kg/day downregulated the expression of pendrin and led to a decrease in AQP2 expression. Enhanced diuresis by probenecid plus HCTZ was not associated with volume depletion. Conclusion: Probenecid pre-treatment downregulates pendrin and robustly enhances diuresis by HCTZ-mediated NCC inhibition in kidney.
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PMID:Probenecid Pre-treatment Downregulates the Kidney Cl-/HCO3- Exchanger (Pendrin) and Potentiates Hydrochlorothiazide-Induced Diuresis. 3005 Apr 51