scholarly journals Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2

2008 ◽  
Vol 294 (4) ◽  
pp. F702-F709 ◽  
Author(s):  
Gheun-Ho Kim ◽  
Nak Won Choi ◽  
Ju-Young Jung ◽  
Ji-Hyun Song ◽  
Chang Hwa Lee ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Urine Osmolality ◽  
Urinary Concentration ◽  
Prostaglandin E ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Cox 2

Prostaglandin E2 may antagonize vasopressin-stimulated salt absorption in the thick ascending limb and water absorption in the collecting duct. Blockade of prostaglandin E2 synthesis by nonsteroidal anti-inflammatory drugs (NSAIDs) enhances urinary concentration, and these agents have antidiuretic effects in patients with nephrogenic diabetes insipidus (NDI) of different etiologies. Because renal prostaglandins are derived largely from cyclooxygenase-2 (COX-2), we hypothesized that treatment of NDI with a COX-2 inhibitor may relieve polyuria through increased expression of Na-K-2Cl cotransporter type 2 (NKCC2) in the thick ascending limb and aquaporin-2 (AQP2) in the collecting duct. To test this hypothesis, semiquantitative immunoblotting and immunohistochemistry were carried out from the kidneys of lithium-induced NDI rats with and without COX-2 inhibition. After male Sprague-Dawley rats were fed an LiCl-containing rat diet for 3 wk, the rats were randomly divided into control and experimental groups. The COX-2 inhibitor DFU (40 mg·kg−1·day−1) was orally administered to the experimental rats for an additional week. Treatment with the COX-2 inhibitor significantly relieved polyuria and raised urine osmolality. Semiquantitative immunoblotting using whole-kidney homogenates revealed that COX-2 inhibition caused significant increases in the abundance of AQP2 and NKCC2. Immunohistochemistry for AQP2 and NKCC2 confirmed the effects of COX-2 inhibition in lithium-induced NDI rats. The upregulation of AQP2 and NKCC2 in response to the COX-2 inhibitor may underlie the therapeutic mechanisms by which NSAIDs enhance antidiuresis in patients with NDI.

Role of arginine vasopressin in medullary thick ascending limb on maximal urinary concentration

1986 ◽  
Vol 251 (2) ◽  
pp. F266-F270 ◽  
Author(s):  
J. K. Kim ◽  
S. N. Summer ◽  
A. E. Erickson ◽  
R. W. Schrier
Keyword(s):  
Adenylate Cyclase ◽  
Arginine Vasopressin ◽  
Urinary Concentration ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Urinary Osmolality ◽  
Medullary Thick Ascending Limb ◽  
Sprague Dawley Rats ◽  
Collecting Tubules

Two groups of Sprague-Dawley rats, Harlan (H) and Charles River (CR), were discovered in that the medullary thick ascending limb (MAL) had a profoundly different adenylate cyclase response to arginine vasopressin (AVP). Using these two groups of rats, we studied the correlation between AVP action on the MAL and maximal urinary concentration. AVP (10(-6) M) significantly stimulated adenylate cyclase in MAL of H rats (7.4 +/- 0.9 to 43.8 +/- 4.6 fmol cAMP formed X 30 min-1 X mm-1, P less than 0.001) but not in CR rats (10.3 +/- 1.4 to 12.7 +/- 2.0 fmol cAMP formed X 30 min-1 X mm-1, NS). In contrast, AVP significantly stimulated adenylate cyclase of cortical, outer and inner medullary collecting tubules from both H and CR rats. Glucagon (10(-6) M) significantly stimulated adenylate cyclase of MAL from both H and CR rats. After 48 h of fluid deprivation, urinary osmolality was significantly higher (P less than 0.001) in the H (4,504 +/- 399 mosmol/kg H2O, n = 14) than CR (2,840 +/- 176 mosmol/kg H2O, n = rats. This observation was not attributable to differences in creatinine clearance (CR, 1.30 +/- 0.24; H, 1.24 +/- 0.03 ml/min, NS, n = 4) or plasma AVP (CR, 12.75 +/- 1.44; H, 12.38 +/- 1.17 pg/ml, NS, n = 6) levels. These results therefore suggest that the action of AVP on the MAL, in addition to the effect on collecting tubules, is involved in maximal urinary concentration in rats.

scholarly journals Renal phenotype in Bardet-Biedl syndrome: a combined defect of urinary concentration and dilution is associated with defective urinary AQP2 and UMOD excretion

2016 ◽  
Vol 311 (4) ◽  
pp. F686-F694 ◽  
Author(s):  
Miriam Zacchia ◽  
Enza Zacchia ◽  
Enrica Zona ◽  
Giovanna Capolongo ◽  
Ilaria Raiola ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Urine Osmolality ◽  
Normal Function ◽  
Urinary Concentration ◽  
Thick Ascending Limb ◽  
Renal Anomalies ◽  
Bardet Biedl Syndrome ◽  
Urine Albumin ◽  
Plasma Factor ◽  
Renal Phenotype

The renal phenotype in Bardet-Biedl syndrome (BBS) is highly variable. The present study describes renal findings in 41 BBS patients and analyzes the pathogenesis of hyposthenuria, the most common renal dysfunction. Five of 41 patients (12%) showed an estimated glomerular filtration rate < 60 ml·min−1·1.73 m−2. Urine protein and urine albumin-to-creatinine ratio were over 200 and 30 mg/g in 9/24 and 7/23 patients, respectively. Four of 41 patients showed no renal anomalies on ultrasound. Twenty of 34 patients had hyposthenuria in the absence of renal insufficiency. In all 8 of the hyposthenuric patients studied, dDAVP failed to elevate urine osmolality (Uosm), suggesting a nephrogenic origin. Interestingly, water loading (WL) did not result in a significant reduction of Uosm, indicating combined concentrating and diluting defects. dDAVP infusion induced a significant increase of plasma Factor VIII and von Willebrand Factor levels, supporting normal function of the type 2 vasopressin receptor at least in endothelial cells. While urinary aquaporin 2 (u-AQP2) abundance was not different between patients and controls at baseline, the dDAVP-induced increased u-AQP2 and the WL-induced reduction of u-AQP2 were blunted in patients with a combined concentrating and diluting defect, suggesting a potential role of AQP2 in the defective regulation of water absorption. Urine Uromodulin excretion was reduced in all hyposthenuric patients, suggesting a thick ascending limb defect. Interestingly, renal Na, Cl, Ca, but not K handling was impaired after acute WL but not at basal. In summary, BBS patients show combined urinary concentration and dilution defects; a thick ascending limb and collecting duct tubulopathy may underlie impaired water handling.

Immunolocalization of ectonucleotidases along the rat nephron

2006 ◽  
Vol 290 (2) ◽  
pp. F550-F560 ◽  
Author(s):  
Renu M. Vekaria ◽  
David G. Shirley ◽  
Jean Sévigny ◽  
Robert J. Unwin
Keyword(s):  
Collecting Duct ◽  
Distal Tubule ◽  
Extracellular Nucleotides ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Low Level ◽  
Amplification Method ◽  
Sprague Dawley Rats ◽  
Collecting Ducts ◽  
Calbindin D

Evidence is accumulating that extracellular nucleotides act as autocrine/paracrine agents in most tissues, including the kidneys. Several families of surface-located enzymes, collectively known as ectonucleotidases, can degrade nucleotides. Using immunohistochemistry, we have examined the segmental distribution of five ectonucleotidases along the rat nephron. Perfusion-fixed kidneys were obtained from anesthetized male Sprague-Dawley rats. Cryostat sections of cortical and medullary regions were incubated with antibodies specific to the following enzymes: ectonucleoside triphosphate diphosphohydrolase (NTPDase) 1, NTPDase2, NTPDase3, ectonucleotide pyrophosphatase phosphodiesterase 3 (NPP3), and ecto-5′-nucleotidase. Sections were then costained with Phaseolus vulgaris erythroagglutinin (for identification of proximal tubules) and antibodies against Tamm-Horsfall protein (for identification of thick ascending limb), calbindin-D28k (for identification of distal tubule), and aquaporin-2 (for identification of collecting duct). The tyramide signal amplification method was used when the ectonucleotidase and marker antibody were raised in the same species. The glomerulus expressed NTPDase1 and NPP3. The proximal tubule showed prominent expression of NPP3 and ecto-5′-nucleotidase in most, but not all, segments. NTPDase2 and NTPDase3, but not NPP3 or ecto-5′-nucleotidase, were expressed in the thick ascending limb and distal tubule. NTPDase3, with some low-level expression of ecto-5′-nucleotidase, was also found in cortical and outer medullary collecting ducts. Inner medullary collecting ducts displayed low-level staining for NTPDase1, NTPDase2, NTPDase3, and ecto-5′-nucleotidase. We conclude that these ectonucleotidases are differentially expressed along the nephron and may play a key role in activation of purinoceptors by nucleotides and nucleosides.

Sepsis induces an increase in thick ascending limb Cox-2 that is TLR4 dependent

2007 ◽  
Vol 293 (4) ◽  
pp. F1187-F1196 ◽  
Author(s):  
Tarek M. El-Achkar ◽  
Zoya Plotkin ◽  
Branislav Marcic ◽  
Pierre C. Dagher
Keyword(s):  
Rat Kidney ◽  
Cecal Ligation ◽  
Thick Ascending Limb ◽  
Wild Type ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tlr4 Gene ◽  
Cox 2 ◽  
Tlr4 Activation ◽  
Induced Changes

Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for the formation of inflammatory prostanoids such as prostaglandins and thromboxane. Its role in the pathophysiology of inflammatory states like sepsis is increasingly recognized. Recently, we demonstrated that sepsis upregulates the endotoxin receptor Toll-like receptor 4 (TLR4) in rat kidney. Because Cox-2 is one of the downstream products of TLR4 activation, we hypothesized that sepsis-induced changes in renal Cox-2 expression are TLR4 dependent. Indeed, we show that in Sprague-Dawley rats, cecal ligation and puncture (a sepsis model) increases Cox-2 expression in cortical and medullary thick ascending loops (cTAL and mTAL, respectively) as well as inner medullary collecting ducts. These are all sites of increased TLR4 expression during sepsis. To determine the actual dependence on TLR4, we measured Cox-2 expression in wild-type and mutant mice which harbor a TLR4 gene deletion ( TLR4−/−). In wild-type mice, sepsis increased Cox-2 expression in proximal tubules, cTAL, and mTAL. In contrast, septic TLR4−/− mice showed no significant increase in cTAL or mTAL Cox-2 expression. Furthermore, renin was absent from juxtaglomerular cells of TLR4−/− mice. We conclude that the dependence of sepsis-induced renal Cox-2 expression on TLR4 is tubule specific. The TLR4-dependent Cox-2 expression is mostly restricted to cortical and medullary thick ascending loops of Henle that characteristically express and secrete Tamm-Horsfall protein.

scholarly journals Potential involvement of P2Y2 receptor in diuresis of postobstructive uropathy in rats

2010 ◽  
Vol 298 (3) ◽  
pp. F634-F642 ◽  
Author(s):  
Yue Zhang ◽  
Donald E. Kohan ◽  
Raoul D. Nelson ◽  
Noel G. Carlson ◽  
Bellamkonda K. Kishore
Keyword(s):  
Mrna Expression ◽  
Collecting Duct ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Urinary Concentration ◽  
Sham Operation ◽  
Protein Abundance ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Relative Mrna Expression

AVP resistance of the medullary collecting duct (mCD) in postobstructive uropathy (POU) has been attributed to increased production of PGE2. P2Y2 receptor activation causes production of PGE2 by the mCD. We hypothesize that increased P2Y2 receptor expression and/or activity may contribute to the diuresis of POU. Sprague-Dawley rats were subjected to bilateral ureteral obstruction for 24 h followed by release (BUO/R, n = 17) or sham operation (SHM/O, n = 15) and euthanized after 1 wk or 12 days. BUO/R rats developed significant polydipsia, polyuria, urinary concentration defect, and increased urinary PGE2 and decreased aquaporin-2 protein abundance in the inner medulla compared with SHM/O rats. After BUO/R, the relative mRNA expression of P2Y2 and P2Y6 receptors was increased by 2.7- and 4.9-fold, respectively, without significant changes in mRNA expression of P2Y1 or P2Y4 receptor. This was associated with a significant 3.5-fold higher protein abundance of the P2Y2 receptor in BUO/R than SHM/O rats. When freshly isolated mCD fractions were challenged with different types of nucleotides (ATPγS, ADP, UTP, or UDP), BUO/R and SHM/O rats responded to only ATPγS and UTP and released PGE2, consistent with involvement of the P2Y2, but not P2Y6, receptor. ATPγS- or UTP-stimulated increases in PGE2 were much higher in BUO/R (3.20- and 2.28-fold, respectively, vs. vehicle controls) than SHM/O (1.68- and 1.30-fold, respectively, vs. vehicle controls) rats. In addition, there were significant 2.4- and 2.1-fold increases in relative mRNA expression of prostanoid EP1 and EP3 receptors, respectively, in the inner medulla of BUO/R vs. SHM/O rats. Taken together, these data suggest that increased production of PGE2 by the mCD in POU may be due to increased expression and activity of the P2Y2 receptor. Increased mRNA expression of EP1 and EP3 receptors in POU may also help accentuate PGE2-induced signaling in the mCD.

Inherited secondary nephrogenic diabetes insipidus: concentrating on humans

2013 ◽  
Vol 304 (8) ◽  
pp. F1037-F1042 ◽  
Author(s):  
D. Bockenhauer ◽  
D. G. Bichet
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Lithium Treatment ◽  
Water Channel ◽  
Underlying Mechanism ◽  
Bartter Syndrome ◽  
Experimental Models ◽  
Urinary Concentration ◽  
Apparent Mineralocorticoid Excess

The study of human physiology is paramount to understanding disease and developing rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentration and identified the vasopressin receptor AVPR2, as well as the water channel aquaporin-2 (AQP2), as key players in water reabsorption in the collecting duct. Yet, there are also secondary forms of NDI, for instance as a complication of lithium treatment. The focus of this review is secondary NDI associated with inherited human diseases, such as Bartter syndrome or apparent mineralocorticoid excess. Currently, the underlying pathophysiology of this inherited secondary NDI is unclear, but there appears to be true AQP2 deficiency. To better understand the underlying mechanism(s), collaboration between clinical and experimental physiologists is essential to further investigate these observations in appropriate experimental models.

scholarly journals Nephrogenic diabetes insipidus in mice caused by deleting COOH-terminal tail of aquaporin-2

2007 ◽  
Vol 292 (5) ◽  
pp. F1334-F1344 ◽  
Author(s):  
Peijun P. Shi ◽  
Xiao R. Cao ◽  
Jing Qu ◽  
Ken A. Volk ◽  
Patricia Kirby ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Hormonal Regulation ◽  
Nephrogenic Diabetes Insipidus ◽  
Mdck Cells ◽  
Collecting Duct ◽  
Phosphorylation Site ◽  
Water Channel ◽  
Urine Osmolality ◽  
Functional Expression ◽  
Aquaporin 2

In mammals, the hormonal regulation of water homeostasis is mediated by the aquaporin-2 water channel (Aqp2) of the collecting duct (CD). Vasopressin induces redistribution of Aqp2 from intracellular vesicles to the apical membrane of CD principal cells, accompanied by increased water permeability. Mutations of AQP2 gene in humans cause both recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. In this study, we generated a line of mice with the distal COOH-terminal tail of the Aqp2 deleted ( Aqp2Δ 230), including the protein kinase A phosphorylation site (S256), but still retaining the putative apical localization signal (221–229) at the COOH-terminal. Mice heterozygous for the truncation appear normal. Homozygotes are viable to adulthood, with reduced urine concentrating capacity, increased urine output, decreased urine osmolality, and increased daily water consumption. Desmopressin increased urine osmolality in wild-type mice but had no effect on Aqp2Δ 230/Δ 230 mice. Kidneys from affected mice showed CD and pelvis dilatation and papillary atrophy. By immunohistochemical and immunoblot analyses using antibody against the NH2-terminal region of the protein Aqp2Δ 230/Δ 230 mice had a markedly reduced protein abundance. Expression of the truncated protein in MDCK cells was consistent with a small amount of functional expression but no stimulation. Thus we have generated a mouse model of NDI that may be useful in studying the physiology and potential therapy of this disease.

Group VIA phospholipase A2 is a target for vasopressin signaling in the thick ascending limb

2012 ◽  
Vol 302 (7) ◽  
pp. F865-F874 ◽  
Author(s):  
A. Paliege ◽  
T. Roeschel ◽  
H. Neymeyer ◽  
S. Seidel ◽  
T. Kahl ◽  
...  
Keyword(s):  
Gene Expression Analysis ◽  
Urine Concentration ◽  
Prostaglandin E ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Outer Medulla ◽  
Sprague Dawley Rats ◽  
Β Protein ◽  
Bromoenol Lactone ◽  
V2 Receptor

Na+-K+-2Cl− cotransporter (NKCC2)-mediated NaCl reabsorption in the thick ascending limb (TAL) is stimulated by AVP via V2 receptor/PKA/cAMP signaling. This process is antagonized by locally produced eicosanoids such as 20-HETE or prostaglandin E2, which are synthesized in a phospholipase A2-dependent reaction cascade. Using microarray-based gene expression analysis, we found evidence for an AVP-dependent downregulation of the calcium-independent isoform of PLA2, iPLA2β, in the outer medulla of rats. In the present study, we therefore examined the contribution of iPLA2β to NKCC2 regulation. Immunoreactive iPLA2β protein was detected in cultured mTAL cells as well as in the entire TAL of rodents and humans with the exception of the macula densa. Administration of the V2 receptor-selective agonist desmopressin (5 ng/h; 3 days) to AVP-deficient diabetes insipidus rats increased outer medullary phosphorylated NKCC2 (pNKCC2) levels more than twofold in association with a marked reduction in iPLA2β abundance (−65%; P < 0.05), thus confirming microarray results. Inhibition of iPLA2β in Sprague-Dawley rats with FKGK 11 (0.5 μM) or in mTAL cells with FKGK 11 (10 μM) or ( S)-bromoenol lactone (5 μM) for 1 h markedly increased pNKCC2 levels without affecting total NKCC2 expression. Collectively, these data indicate that iPLA2β acts as an inhibitory modulator of NKCC2 activity and suggest that downregulation of iPLA2β may be a relevant step in AVP-mediated urine concentration.

Cyclophosphamide-induced vasopressin-independent activation of aquaporin-2 in the rat kidney

2015 ◽  
Vol 309 (5) ◽  
pp. F474-F483 ◽  
Author(s):  
Sua Kim ◽  
Hyo-Jung Choi ◽  
Chor Ho Jo ◽  
Joon-Sung Park ◽  
Tae-Hwan Kwon ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Rat Kidney ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Pcr Analysis ◽  
Urinary Concentration ◽  
Sprague Dawley ◽  
Aquaporin 2 ◽  
Sprague Dawley Rats

Because cyclophosphamide-induced hyponatremia was reported to occur without changes in plasma vasopressin in a patient with central diabetes insipidus, we hypothesized that cyclophosphamide or its active metabolite, 4-hydroperoxycyclophosphamide (4-HC), may directly dysregulate the expression of water channels or sodium transporters in the kidney. To investigate whether intrarenal mechanisms for urinary concentration are activated in vivo and in vitro by treatment with cyclophosphamide and 4-HC, respectively, we used water-loaded male Sprague-Dawley rats, primary cultured inner medullary collecting duct (IMCD) cells, and IMCD suspensions prepared from male Sprague-Dawley rats. In cyclophosphamide-treated rats, significant increases in renal expression of aquaporin-2 (AQP2) and Na-K-2Cl cotransporter type 2 (NKCC2) were shown by immunoblot analysis and immunohistochemistry. Apical translocation of AQP2 was also demonstrated by quantitative immunocytochemistry. In both rat kidney and primary cultured IMCD cells, significant increases in AQP2 and vasopressin receptor type 2 (V2R) mRNA expression were demonstrated by real-time quantitative PCR analysis. Confocal laser-scanning microscopy revealed that apical translocation of AQP2 was remarkably increased when primary cultured IMCD cells were treated with 4-HC in the absence of vasopressin stimulation. Moreover, AQP2 upregulation and cAMP accumulation in response to 4-HC were significantly reduced by tolvaptan cotreatment in primary cultured IMCD cells and IMCD suspensions, respectively. We demonstrated that, in the rat kidney, cyclophosphamide may activate V2R and induce upregulation of AQP2 in the absence of vasopressin stimulation, suggesting the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis (NSIAD).

scholarly journals Renal cortical regulation of COX-1 and functionally related products in early renovascular hypertension (rat)

2006 ◽  
Vol 291 (5) ◽  
pp. F987-F994 ◽  
Author(s):  
F. Theilig ◽  
H. Debiec ◽  
B. Nafz ◽  
P. Ronco ◽  
R. Nüsing ◽  
...  
Keyword(s):  
Renovascular Hypertension ◽  
Collecting Duct ◽  
Distal Tubule ◽  
Prostaglandin E ◽  
Thick Ascending Limb ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Cortical Collecting Duct ◽  
Cox 2 ◽  
Cox 1

Renal volume regulation is modulated by the action of cyclooxygenases (COX) and the resulting generation of prostanoids. Epithelial expression of COX isoforms in the cortex directs COX-1 to the distal convolutions and cortical collecting duct, and COX-2 to the thick ascending limb. Partly colocalized are prostaglandin E synthase (PGES), the downstream enzyme for renal prostaglandin E2 (PGE2) generation, and the EP receptors type 1 and 3. COX-1 and related components were studied in two kidney-one clip (2K1C) Goldblatt hypertensive rats with combined chronic ANG II or bradykinin B2 receptor blockade using candesartan (cand) or the B2 antagonist Hoechst 140 (Hoe). Rats (untreated sham, 2K1C, sham + cand, 2K1C + cand, sham + Hoe, 2K1C + Hoe) were treated to map expression of parameters controlling PGE2 synthesis. In 2K1C, cortical COX isoforms did not change uniformly. COX-2 changed in parallel with NO synthase 1 (NOS1) expression with a raise in the clipped, but a decrease in the nonclipped side. By contrast, COX-1 and PGES were uniformly downregulated in both kidneys, along with reduced urinary PGE2 levels, and showed no clear relations with the NO status. ANG II receptor blockade confirmed negative regulation of COX-2 by ANG II but blunted the decrease in COX-1 selectively in nonclipped kidneys. B2 receptor blockade reduced COX-2 induction in 2K1C but had no clear effect on COX-1. We suggest that in 2K1C, COX-1 and PGES expression may fail to oppose the effects of renovascular hypertension through reduced prostaglandin signaling in late distal tubule and cortical collecting duct.

Sign in / Sign up

Export Citation Format

Share Document