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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.
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10 MeSH Terms
Anatomically-specific intratubular and interstitial biominerals in the human renal medullo-papillary complex.
Chen L, Hsi RS, Yang F, Sherer BA, Stoller ML, Ho SP
(2017) PLoS One 12: e0187103
MeSH Terms: Humans, Kidney Medulla, Microscopy, Electron, Transmission, Minerals, Tomography, X-Ray Computed
Show Abstract · Added January 16, 2018
Limited information exists on the anatomically-specific early stage events leading to clinically detectable mineral aggregates in the renal papilla. In this study, quantitative multiscale correlative maps of structural, elemental and biochemical properties of whole medullo-papillary complexes from human kidneys were developed. Correlative maps of properties specific to the uriniferous and vascular tubules using high-resolution X-ray computed tomography, scanning and transmission electron microscopy, energy dispersive X-ray spectroscopy, and immunolocalization of noncollagenous proteins (NCPs) along with their association with anatomy specific biominerals were obtained. Results illustrated that intratubular spherical aggregates primarily form at the proximal regions distant from the papillary tip while interstitial spherical and fibrillar aggregates are distally located near the papillary tip. Biominerals at the papillary tip were closely localized with 10 to 50 μm diameter vasa recta immunolocalized for CD31 inside the medullo-papillary complex. Abundant NCPs known to regulate bone mineralization were localized within nanoparticles, forming early pathologic mineralized regions of the complex. Based on the physical association between vascular and urothelial tubules, results from light and electron microscopy techniques suggested that these NCPs could be delivered from vasculature to prompt calcification of the interstitial regions or they might be synthesized from local vascular smooth muscle cells after transdifferentiation into osteoblast-like phenotypes. In addition, results provided insights into the plausible temporal events that link the anatomically specific intratubular mineral aggregates with the interstitial biomineralization processes within the functional unit of the kidney.
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5 MeSH Terms
The origins of urinary stone disease: upstream mineral formations initiate downstream Randall's plaque.
Hsi RS, Ramaswamy K, Ho SP, Stoller ML
(2017) BJU Int 119: 177-184
MeSH Terms: Calcinosis, Humans, Kidney Diseases, Kidney Medulla, Minerals, Urinary Calculi
Show Abstract · Added January 16, 2018
OBJECTIVES - To describe a new hypothesis for the initial events leading to urinary stones. A biomechanical perspective on Randall's plaque formation through form and function relationships is applied to functional units within the kidney, we have termed the 'medullo-papillary complex' - a dynamic relationship between intratubular and interstitial mineral aggregates.
METHODS - A complete MEDLINE search was performed to examine the existing literature on the anatomical and physiological relationships in the renal medulla and papilla. Sectioned human renal medulla with papilla from radical nephrectomy specimens were imaged using a high resolution micro X-ray computed tomography. The location, distribution, and density of mineral aggregates within the medullo-papillary complex were identified.
RESULTS - Mineral aggregates were seen proximally in all specimens within the outer medulla of the medullary complex and were intratubular. Distal interstitial mineralisation at the papillary tip corresponding to Randall's plaque was not seen until a threshold of proximal mineralisation was observed. Mineral density measurements suggest varied chemical compositions between the proximal intratubular (330 mg/cm ) and distal interstitial (270 mg/cm ) deposits. A review of the literature revealed distinct anatomical compartments and gradients across the medullo-papillary complex that supports the empirical observations that proximal mineralisation triggers distal Randall's plaque formation.
CONCLUSION - The early stone event is initiated by intratubular mineralisation of the renal medullary tissue leading to the interstitial mineralisation that is observed as Randall's plaque. We base this novel hypothesis on a multiscale biomechanics perspective involving form and function relationships, and empirical observations. Additional studies are needed to validate this hypothesis.
© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.
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6 MeSH Terms
Short forms of Ste20-related proline/alanine-rich kinase (SPAK) in the kidney are created by aspartyl aminopeptidase (Dnpep)-mediated proteolytic cleavage.
Markadieu N, Rios K, Spiller BW, McDonald WH, Welling PA, Delpire E
(2014) J Biol Chem 289: 29273-84
MeSH Terms: Amino Acid Sequence, Animals, Blood Pressure, Cloning, Molecular, Glutamyl Aminopeptidase, Humans, Kidney, Kidney Medulla, Mass Spectrometry, Metalloproteases, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Oocytes, Protein Binding, Protein Structure, Secondary, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Signal Transduction, Sodium, Xenopus laevis
Show Abstract · Added October 21, 2014
The Ste20-related kinase SPAK regulates sodium, potassium, and chloride transport in a variety of tissues. Recently, SPAK fragments, which lack the catalytic domain and are inhibitory to Na(+) transporters, have been detected in kidney. It has been hypothesized that the fragments originate from alternative translation start sites, but their precise origin is unknown. Here, we demonstrate that kidney lysate possesses proteolytic cleavage activity toward SPAK. Ion exchange and size exclusion chromatography combined with mass spectrometry identified the protease as aspartyl aminopeptidase. The presence of the protease was verified in the active fractions, and recombinant aspartyl aminopeptidase recapitulated the cleavage pattern observed with kidney lysate. Identification of the sites of cleavage by mass spectrometry allowed us to test the function of the smaller fragments and demonstrate their inhibitory action toward the Na(+)-K(+)-2Cl(-) cotransporter, NKCC2.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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21 MeSH Terms
Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice.
Zeng F, Miyazawa T, Kloepfer LA, Harris RC
(2014) Kidney Int 86: 538-47
MeSH Terms: Animals, Apoptosis, Blood Urea Nitrogen, Caspase 3, Cell Proliferation, Cyclin D, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Disease Models, Animal, Disease Progression, Epithelial Cells, Fibrosis, Gene Deletion, Kidney Cortex, Kidney Medulla, Mice, Organ Size, Polycystic Kidney Diseases, Receptor, ErbB-4
Show Abstract · Added October 27, 2014
ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios, and elevated BUN levels. No apparent defects in renal development were noted with ErbB4 deletion itself. Increased cell proliferation was predominately seen in the cortex of cystic kidneys with or without ErbB4 deletion. However, there was significantly more cell proliferation in the cyst-lining epithelial cells in cpk mice with ErbB4 deletion. TUNEL staining localized apoptotic cells mainly to the renal medulla. There were significantly more apoptotic cells in the cyst-lining epithelial cells in ErbB4-deleted cpk kidneys, with decreased levels of cyclin D1, increased levels of p21, p27, and cleaved caspase 3. Thus, lack of ErbB4 may contribute to elevated cell proliferation and unbalanced cell apoptosis, resulting in accelerated cyst formation and early renal function deterioration. These studies suggest that the high level of ErbB4 expression seen in cpk mice may exert relative cytoprotective effects in renal epithelia.
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19 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.
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22 MeSH Terms
Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells.
He W, Zhang M, Zhao M, Davis LS, Blackwell TS, Yull F, Breyer MD, Hao CM
(2014) Pflugers Arch 466: 357-367
MeSH Terms: Animals, Benzamides, Cyclooxygenase 2, Enzyme Induction, Kidney Medulla, Male, Mice, Mice, Inbred C57BL, NF-kappa B, Sodium, Sodium Chloride, Dietary
Show Abstract · Added March 7, 2014
High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E2 (PGE2). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium.
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11 MeSH Terms
Membrane-type 4 matrix metalloproteinase (MT4-MMP) modulates water homeostasis in mice.
Srichai MB, Colleta H, Gewin L, Matrisian L, Abel TW, Koshikawa N, Seiki M, Pozzi A, Harris RC, Zent R
(2011) PLoS One 6: e17099
MeSH Terms: Animals, Gene Deletion, Gene Expression Regulation, Enzymologic, Homeostasis, Hypothalamus, Anterior, Kidney Medulla, Matrix Metalloproteinase 17, Mice, Osmolar Concentration, Water
Show Abstract · Added February 25, 2014
MT4-MMP is a membrane-type metalloproteinase (MMP) anchored to the membrane by a glycosyl-phosphatidylinositol (GPI) motif. GPI-type MT-MMPs (MT4- and MT6-MMP) are related to other MT-MMPs, but their physiological substrates and functions in vivo have yet to be identified. In this manuscript we show that MT4-MMP is expressed early in kidney development, as well as in the adult kidney, where the highest levels of expression are found in the papilla. MT4-MMP null mice had minimal renal developmental abnormalities, with a minor branching morphogenesis defect in early embryonic kidney development and slightly dysmorphic collecting ducts in adult mice. Interestingly, MT4-MMP null mice had higher baseline urine osmolarities relative to wild type controls, but these animals were able to concentrate and dilute their urines normally. However, MT4-MMP-null mice had decreased daily water intake and daily urine output, consistent with primary hypodipsia. MT4-MMP was shown to be expressed in areas of the hypothalamus considered important for regulating thirst. Thus, our results show that although MT4-MMP is expressed in the kidney, this metalloproteinase does not play a major role in renal development or function; however it does appear to modify the neural stimuli that modulate thirst.
1 Communities
4 Members
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10 MeSH Terms
Angiotensin II: breathtaking in the renal medulla.
Haase VH
(2011) Kidney Int 79: 269-71
MeSH Terms: Actins, Angiotensin II, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Transdifferentiation, Collagen Type I, Collagen Type III, Fibrosis, Humans, Hydrogen Peroxide, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Medulla, Procollagen-Proline Dioxygenase, Proliferating Cell Nuclear Antigen, Rats, Tissue Inhibitor of Metalloproteinase-1, Up-Regulation, Vimentin
Show Abstract · Added August 19, 2013
Angiotensin II (Ang II) is a major contributor to the progression of renal fibrosis. Wang and colleagues provide evidence that signaling through the prolyl-4-hydroxylase domain (PHD)-hypoxia-inducible factor-1 (HIF-1) pathway mediates profibrotic effects of Ang II in rat renal medullary interstitial cells under normoxic conditions, thus placing the HIF oxygen-sensing pathway into the center of an Ang II-induced profibrotic signaling cascade.
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18 MeSH Terms
Development of a selective small-molecule inhibitor of Kir1.1, the renal outer medullary potassium channel.
Bhave G, Chauder BA, Liu W, Dawson ES, Kadakia R, Nguyen TT, Lewis LM, Meiler J, Weaver CD, Satlin LM, Lindsley CW, Denton JS
(2011) Mol Pharmacol 79: 42-50
MeSH Terms: Animals, Benzimidazoles, Cricetinae, Female, HEK293 Cells, Humans, Kidney Medulla, Mice, Potassium Channel Blockers, Potassium Channels, Potassium Channels, Inwardly Rectifying, Protein Binding, Rats, Xenopus laevis
Show Abstract · Added January 24, 2015
The renal outer medullary potassium (K+) channel, ROMK (Kir1.1), is a putative drug target for a novel class of loop diuretic that would lower blood volume and pressure without causing hypokalemia. However, the lack of selective ROMK inhibitors has hindered efforts to assess its therapeutic potential. In a high-throughput screen for small-molecule modulators of ROMK, we previously identified a potent and moderately selective ROMK antagonist, 7,13-bis(4-nitrobenzyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (VU590), that also inhibits Kir7.1. Because ROMK and Kir7.1 are coexpressed in the nephron, VU590 is not a good probe of ROMK function in the kidney. Here we describe the development of the structurally related inhibitor 2,2'-oxybis(methylene)bis(5-nitro-1H-benzo[d]imidazole) (VU591), which is as potent as VU590 but is selective for ROMK over Kir7.1 and more than 65 other potential off-targets. VU591 seems to block the intracellular pore of the channel. The development of VU591 may enable studies to explore the viability of ROMK as a diuretic target.
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14 MeSH Terms