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Renal Medullary Interstitial COX-2 (Cyclooxygenase-2) Is Essential in Preventing Salt-Sensitive Hypertension and Maintaining Renal Inner Medulla/Papilla Structural Integrity.
Zhang MZ, Wang S, Wang Y, Zhang Y, Ming Hao C, Harris RC
(2018) Hypertension 72: 1172-1179
MeSH Terms: Animals, Apoptosis, Aquaporin 2, Blood Pressure, Cyclooxygenase 2, Epithelial Sodium Channels, Hypertension, Kidney Medulla, Mice, Mice, Transgenic
Show Abstract · Added November 8, 2018
COX (cyclooxygenase)-derived prostaglandins regulate renal hemodynamics and salt and water homeostasis. Inhibition of COX activity causes blood pressure elevation. In addition, chronic analgesic abuse can induce renal injury, including papillary necrosis. COX-2 is highly expressed in the kidney papilla in renal medullary interstitial cells (RMICs). However, its role in blood pressure and papillary integrity in vivo has not been definitively studied. In mice with selective, inducible RMIC COX-2 deletion, a high-salt diet led to an increase in blood pressure that peaked at 4 to 5 weeks and was associated with increased papillary expression of AQP2 (aquaporin 2) and ENac (epithelial sodium channel) and decreased expression of cystic fibrosis transmembrane conductance regulator. With continued high-salt feeding, the mice with RMIC COX-2 deletion had progressive decreases in blood pressure from its peak. After return to a normal-salt diet for 3 weeks, blood pressure remained low and was associated with a persistent urinary concentrating defect. Within 2 weeks of institution of a high-salt diet, increased apoptotic RMICs and collecting duct cells could be detected in papillae with RMIC deletion of COX-2, and by 9 weeks of high salt, there was a striking loss of the papillae. Therefore, RMIC COX-2 expression plays a crucial role in renal handling water and sodium homeostasis, preventing salt-sensitive hypertension and maintaining structural integrity of papilla.
1 Communities
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10 MeSH Terms
Generation of a tenascin-C-CreER2 knockin mouse line for conditional DNA recombination in renal medullary interstitial cells.
He W, Xie Q, Wang Y, Chen J, Zhao M, Davis LS, Breyer MD, Gu G, Hao CM
(2013) PLoS One 8: e79839
MeSH Terms: Animals, Aquaporin 1, Aquaporin 2, Crosses, Genetic, Cyclooxygenase 2, Female, Fibroblasts, Founder Effect, Gene Expression Regulation, Gene Knock-In Techniques, Genes, Reporter, Green Fluorescent Proteins, Integrases, Kidney Medulla, Lac Operon, Male, Mice, Mice, Transgenic, Promoter Regions, Genetic, Tamoxifen, Tenascin, Transgenes
Show Abstract · Added January 10, 2014
Renal medullary interstitial cells (RMIC) are specialized fibroblast-like cells that exert important functions in maintaining body fluid homeostasis and systemic blood pressure. Here, we generated a RMIC specific tenascin-C promoter driven inducible CreER2 knockin mouse line with an EGFP reporter. Similar as endogenous tenascin-C expression, the reporter EGFP expression in the tenascin-C-CreER2(+/-) mice was observed in the inner medulla of the kidney, and co-localized with COX2 but not with AQP2 or AQP1, suggesting selective expression in RMICs. After recombination (tenascin-C-CreER2(+/-)/ROSA26-lacZ(+/-) mice + tamoxifen), β-gal activity was restricted to the cells in the inner medulla of the kidney, and didn't co-localize with AQP2, consistent with selective Cre recombinase activity in RMICs. Cre activity was not obvious in other major organs or without tamoxifen treatment. This inducible RMIC specific Cre mouse line should therefore provide a novel tool to manipulate genes of interest in RMICs.
1 Communities
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22 MeSH Terms
Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice.
Zhang MZ, Yao B, Wang S, Fan X, Wu G, Yang H, Yin H, Yang S, Harris RC
(2011) J Clin Invest 121: 2845-54
MeSH Terms: Aldosterone, Animals, Aquaporin 2, Aromatic-L-Amino-Acid Decarboxylases, Cyclooxygenase 2, Dopamine, Hypertension, Kidney, Kidney Tubules, Proximal, Longevity, Mice, Mice, Knockout, Receptors, Drug, Renin, Sodium-Bicarbonate Symporters, Sodium-Hydrogen Exchanger 3, Sodium-Hydrogen Exchangers, Sodium-Potassium-Chloride Symporters, Solute Carrier Family 12, Member 1, Solute Carrier Family 12, Member 3, Symporters
Show Abstract · Added December 10, 2013
In addition to its role as an essential neurotransmitter, dopamine serves important physiologic functions in organs such as the kidney. Although the kidney synthesizes dopamine through the actions of aromatic amino acid decarboxylase (AADC) in the proximal tubule, previous studies have not discriminated between the roles of extrarenal and intrarenal dopamine in the overall regulation of renal function. To address this issue, we generated mice with selective deletion of AADC in the kidney proximal tubules (referred to herein as ptAadc-/- mice), which led to selective decreases in kidney and urinary dopamine. The ptAadc-/- mice exhibited increased expression of nephron sodium transporters, decreased natriuresis and diuresis in response to l-dihydroxyphenylalanine, and decreased medullary COX-2 expression and urinary prostaglandin E2 excretion and developed salt-sensitive hypertension. They had increased renin expression and altered renal Ang II receptor (AT) expression, with increased AT1b and decreased AT2 and Mas expression, associated with increased renal injury in response to Ang II. They also exhibited a substantially shorter life span compared with that of wild-type mice. These results demonstrate the importance of the intrarenal dopaminergic system in salt and water homeostasis and blood pressure control. Decreasing intrarenal dopamine subjects the kidney to unbuffered responses to Ang II and results in the development of hypertension and a dramatic decrease in longevity.
1 Communities
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21 MeSH Terms
Protective effects of PPARγ agonist in acute nephrotic syndrome.
Zuo Y, Yang HC, Potthoff SA, Najafian B, Kon V, Ma LJ, Fogo AB
(2012) Nephrol Dial Transplant 27: 174-81
MeSH Terms: Actinin, Acute Disease, Animals, Antibiotics, Antineoplastic, Aquaporin 2, Blotting, Western, Cells, Cultured, Desmin, Epithelial Sodium Channels, Hypoglycemic Agents, Immunoenzyme Techniques, Male, Nephrotic Syndrome, PPAR gamma, Pioglitazone, Podocytes, Proteinuria, Puromycin Aminonucleoside, Rats, Rats, Sprague-Dawley, Thiazolidinediones, Water-Electrolyte Balance
Show Abstract · Added January 24, 2012
BACKGROUND - Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have beneficial effects on renal structure and function in models of diabetes and chronic kidney diseases. However, the increased incidence of weight gain and edema potentially limits their usefulness. We studied an acute minimal-change disease-like nephrotic syndrome model to assess effects of PPARγ agonist on acute podocyte injury and effects on fluid homeostasis.
METHODS - Acute podocyte injury and nephrotic syndrome were induced by puromycin aminonucleoside (PAN) injection in rats.
RESULTS - PPARγ agonist, given at the time or after, but not before PAN, reduced proteinuria, restored synaptopodin, decreased desmin and trended to improve foot process effacement. There was no significant difference in glomerular filtration, effective circulating volume, blood pressure or fractional sodium excretion. PAN-injured podocytes had decreased PPARγ, less nephrin and α-actinin-4, more apoptosis and reduced phosphorylated Akt. In PAN-injured cultured podocytes, PPARγ agonist also reversed abnormalities only when given simultaneously or after injury.
CONCLUSIONS - These results show that PPARγ agonist has protective effects on podocytes in acute nephrotic syndrome without deleterious effects on fluid homeostasis. PPARγ agonist-induced decrease in proteinuria in acute nephrotic syndrome is dependent at least partially on regulation of peroxisome proliferator-response element-sensitive gene expression such as α-actinin-4 and nephrin and the restoration of podocyte structure.
2 Communities
2 Members
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22 MeSH Terms
Sodium and potassium balance depends on αENaC expression in connecting tubule.
Christensen BM, Perrier R, Wang Q, Zuber AM, Maillard M, Mordasini D, Malsure S, Ronzaud C, Stehle JC, Rossier BC, Hummler E
(2010) J Am Soc Nephrol 21: 1942-51
MeSH Terms: Aldosterone, Animals, Aquaporin 2, Epithelial Sodium Channels, Female, Homeostasis, Kidney Cortex, Kidney Tubules, Kidney Tubules, Collecting, Male, Mice, Mice, Knockout, Mice, Transgenic, Potassium, Sodium, Sodium, Dietary
Show Abstract · Added September 9, 2013
Mutations in α, β, or γ subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of αENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking αENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of αENaC in the CCD and weak αENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, αENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing.
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16 MeSH Terms
Assessing the application of tissue microarray technology to kidney research.
Zhang MZ, Su Y, Yao B, Zheng W, Decaestecker M, Harris RC
(2010) J Histochem Cytochem 58: 413-20
MeSH Terms: Angiotensin II Type 1 Receptor Blockers, Animals, Aquaporin 2, Connective Tissue Growth Factor, Cyclooxygenase 2, Fixatives, Immunohistochemistry, Kidney, Mice, Mucoproteins, Rats, Renin, Tissue Array Analysis, Tissue Fixation, Uromodulin
Show Abstract · Added December 10, 2013
Tissue microarray (TMA) is a new high-throughput method that enables simultaneous analysis of the profiles of protein expression in multiple tissue samples. TMA technology has not previously been adapted for physiological and pathophysiological studies of rodent kidneys. We have evaluated the validity and reliability of using TMA to assess protein expression in mouse and rat kidneys. A representative TMA block that we have produced included: (1) mouse and rat kidney cortex, outer medulla, and inner medulla fixed with different fixatives; (2) rat kidneys at different stages of development fixed with different fixatives; (3) mouse and rat kidneys with different physiological or pathophysiological treatments; and (4) built-in controls. As examples of the utility, immunostaining for cyclooxygenase-2, renin, Tamm Horsfall protein, aquaporin-2, connective tissue growth factor, and synaptopodin was carried out with kidney TMA slides. Quantitative analysis of cyclooxygense-2 expression in kidneys confirms that individual cores provide meaningful representations comparable to whole-kidney sections. These studies show that kidney TMA technique is a promising and useful tool for investigating the expression profiles of proteins of interest in rodent kidneys under different physiological and pathophysiological conditions.
3 Communities
3 Members
0 Resources
15 MeSH Terms
GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity.
Rao R, Patel S, Hao C, Woodgett J, Harris R
(2010) J Am Soc Nephrol 21: 428-37
MeSH Terms: Adenylyl Cyclases, Animals, Antidiuretic Agents, Aquaporin 2, Cells, Cultured, Colforsin, Cyclic AMP, Deamino Arginine Vasopressin, Female, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Kidney Concentrating Ability, Kidney Tubules, Collecting, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA, Messenger, Water Deprivation, Water-Electrolyte Balance
Show Abstract · Added August 19, 2013
Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.
1 Communities
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20 MeSH Terms
Urine concentrating defect in prostaglandin EP1-deficient mice.
Kennedy CR, Xiong H, Rahal S, Vanderluit J, Slack RS, Zhang Y, Guan Y, Breyer MD, Hébert RL
(2007) Am J Physiol Renal Physiol 292: F868-75
MeSH Terms: Animals, Aquaporin 2, Arginine Vasopressin, Deamino Arginine Vasopressin, Kidney Concentrating Ability, Mice, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP1 Subtype, Water Deprivation
Show Abstract · Added August 13, 2010
We investigated the role of the prostaglandin E(2) (PGE(2)) EP(1) receptor in modulating urine concentration as it is expressed along the renal collecting duct where arginine-vasopressin (AVP) exerts its anti-diuretic activity, and in the paraventricular and supraoptic nuclei of the hypothalamus where AVP is synthesized. The urine osmolality of EP(1)-null mice (EP(1)(-/-)) failed to match levels achieved by wild-type (WT) counterparts upon water deprivation (WD) for 24 h. This difference was reflected by higher plasma osmolality in WD EP(1)(-/-) mice. Along the collecting duct, the induction and subapical to plasma membrane translocation of the aquaporin-2 water channel in WD EP(1)(-/-) mice appeared equivalent to that of WD WT mice as determined by quantitative RT-PCR and immunohistochemistry. However, medullary interstitial osmolalities dropped significantly in EP(1)(-/-) mice following WD. Furthermore, urinary AVP levels of WD EP(1)(-/-) mice were significantly lower than those of WD WT mice. This deficit could be traced back to a blunted induction of hypothalamic AVP mRNA expression in WD EP(1)(-/-) mice as determined by quantitative RT-PCR. Administration of the AVP mimetic [deamino-Cys(1),D-Arg(8)]-vasopressin restored a significant proportion of the urine concentrating ability of WD EP(1)(-/-) mice. When mice were water loaded to suppress endogenous AVP production, urine osmolalities increased equally for WT and EP(1)(-/-) mice. These data suggest that PGE(2) modulates urine concentration by acting at EP(1) receptors, not in the collecting duct, but within the hypothalamus to promote AVP synthesis in response to acute WD.
1 Communities
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9 MeSH Terms
Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality.
Ge Y, Ahn D, Stricklett PK, Hughes AK, Yanagisawa M, Verbalis JG, Kohan DE
(2005) Am J Physiol Renal Physiol 288: F912-20
MeSH Terms: Animals, Aquaporin 2, Aquaporins, Cyclic AMP, Deamino Arginine Vasopressin, Drinking, Endothelin-1, Integrases, Kidney Tubules, Collecting, Mice, Mice, Knockout, Osmolar Concentration, Promoter Regions, Genetic, Receptors, Vasopressin, Renal Agents, Urine, Vasopressins, Water, Water-Electrolyte Balance
Show Abstract · Added September 9, 2013
In vitro studies suggest that endothelin-1 (ET-1) inhibits vasopressin (AVP)-stimulated water permeability in the collecting duct (CD). To evaluate the role of CD-derived ET-1 in regulating renal water metabolism, the ET-1 gene was selectively disrupted in the CD (CD ET-1 KO). During normal water intake, urinary osmolality (Uosm), plasma Na concentration, urine volume, and renal aquaporin-2 (AQP2) levels were unchanged, but plasma AVP concentration was reduced in CD ET-1 KO animals. CD ET-1 KO mice had impaired ability to excrete an acute, but not a chronic, water load, and this was associated with increased CD ET-1 mRNA in control, but not CD ET-1 KO, mice. In response to continuous infusion of 1-desamino-8-D-arginine vasopressin, CD ET-1 KO mice had greater increases in Uosm, V2 and AQP2 mRNA, and phosphorylation of AQP2. CD suspensions from CD ET-1 KO mice had enhanced AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET-1 KO increases renal sensitivity to the urinary concentrating effects of AVP and suggest that ET-1 functions as a physiological autocrine regulator of AVP action in the CD.
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19 MeSH Terms