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Kidney International Jun 1996Cells of the hypertonic renal medulla accumulate high concentrations of the non-perturbing osmolytes myo-inositol, betaine, and taurine, and are thereby protected from... (Review)
Review
Cells of the hypertonic renal medulla accumulate high concentrations of the non-perturbing osmolytes myo-inositol, betaine, and taurine, and are thereby protected from the perturbing effects of hypertonicity. Kidney-derived MDCK cells accumulate high levels of these three non-perturbing osmolytes when cultured in hypertonic medium and have been used to study their accumulation. The increase in the intracellular concentration of these non-perturbing osmolytes is the result of an increase in the abundance of the mRNA for the specific cotransporter for each osmolyte and the ensuing increase in the activity of the three specific sodium coupled transporters. The increased abundance of mRNA for the myo-inositol and the betaine cotransporters is driven by an increase in the rate of transcription of their genes. We have identified a 13 basepair cis-acting element in the 5' flanking region of the gene for the betaine cotransporter. The element is an enhancer that mediates the transcriptional response to hypertonicity. The protein(s) that binds to the tonicity responsive element is much more active in hypertonic than in isotonic cells, and is in all likelihood the mediator of the transcriptional response to changes in tonicity.
Topics: Animals; Betaine; Carrier Proteins; GABA Plasma Membrane Transport Proteins; Hypertonic Solutions; Inositol 1,4,5-Trisphosphate; Kidney Medulla
PubMed: 8743476
DOI: 10.1038/ki.1996.246 -
Journal of the American Society of... Apr 2018Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism....
Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed from the loop of Henle and collecting ducts. In most tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the angiopoietin receptor endothelial tyrosine kinase 2 (Tie2) or both angiopoietin-1 and angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle-associated protein). Taken together, our data redefine the AVRs as Tie2 signaling-dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla.
Topics: Angiopoietin-1; Angiopoietin-2; Animals; Body Patterning; Cell Lineage; Endothelium, Vascular; Extracellular Fluid; Genes, Reporter; Gestational Age; Homeodomain Proteins; Kidney Concentrating Ability; Kidney Diseases, Cystic; Kidney Medulla; Mice; Mice, Knockout; Mice, Transgenic; Myofibroblasts; Osmosis; Receptor, TIE-2; Renal Circulation; Signal Transduction; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor Receptor-3
PubMed: 29237738
DOI: 10.1681/ASN.2017090962 -
American Journal of Physiology. Renal... Apr 2005EphA2, a member of the large family of Eph receptor tyrosine kinases, is highly expressed in epithelial tissue and has been implicated in cell-cell and cell-matrix...
EphA2, a member of the large family of Eph receptor tyrosine kinases, is highly expressed in epithelial tissue and has been implicated in cell-cell and cell-matrix interactions, as well as cell growth and survival. Expression of EphA2 mRNA and protein was markedly upregulated by both hypertonic stress and by elevated urea concentrations in cells derived from the murine inner medullary collecting duct. This upregulation likely required transactivation of the epidermal growth factor (EGF) receptor tyrosine kinase and metalloproteinase-dependent ectodomain cleavage of an EGF receptor ligand, based on pharmacological inhibitor studies. A human EphA2 promoter fragment spanning nucleotides -4030 to +21 relative to the putative EphA2 transcriptional start site was responsive to tonicity but insensitive to urea. A promoter fragment spanning -1890 to +128 recapitulated both tonicity- and urea-dependent upregulation of expression, consistent with transcriptional activation. Neither the bona fide p53 response element at approximately -1.5 kb nor a pair of putative TonE elements at approximately -3 kb conferred the tonicity responsiveness. EphA2 mRNA and protein were expressed at low levels in rat renal cortex but at high levels in the collecting ducts of the renal medulla and papilla. Water deprivation in rats increased EphA2 expression in renal papilla, whereas dietary supplementation with 20% urea increased EphA2 expression in outer medulla. These data indicate that transcription and expression of the EphA2 receptor tyrosine kinase are regulated by tonicity and urea in vitro and suggest that this phenomenon is also operative in vivo. Renal medullary EphA2 expression may represent an adaptive response to medullary hypertonicity or urea exposure.
Topics: Animals; Cell Line; Gene Expression; Humans; Hypertonic Solutions; In Vitro Techniques; Kidney Medulla; Osmotic Pressure; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, EphA2; Signal Transduction; Urea; Water-Electrolyte Balance
PubMed: 15561974
DOI: 10.1152/ajprenal.00347.2004 -
The American Journal of Pathology Dec 1976A significant number of offspring from brother-sister matings of NIH-Okamoto-Aoki spontaneously hypertensive rats (SHRs) were found to be normotensive at 20 weeks of...
A significant number of offspring from brother-sister matings of NIH-Okamoto-Aoki spontaneously hypertensive rats (SHRs) were found to be normotensive at 20 weeks of age. Over 20% of the animals that were hypertensive at this age had mild-to-moderate unilateral hydronephrosis at the time of sacrifice. In over 90% of the rats that did not develop hypertension spontaneously, ligation of one ureter raised blood pressure above 150 mm Hg within 2 weeks. In those rats made hypertensive by obstructing one ureter and in those that developed hypertension with accompanying naturally occurring hydronephrosis, subcutaneous implants of fragmented renal medulla from unrelated normal rats decreased blood pressure to normotensive levels. In contrast, medullary implants had no significant effect in rats developing hypertension spontaneously without hydronephrosis. Renal inner medullary plasma flow was low in the obstructed kidneys of hydronephrotic hypertensive SHRs but was elevated in the kidneys of nonhydronephrotic hypertensive SHRs. The hypertension in hydronephrotic SHRs appears to be related to an impairment of the antihypertensive function of the renal medulla. Such an impairment of medullary antihypertensive function does not appear to play a significant role in the hypertension in SHRs without hydronephrosis.
Topics: Animals; Hydronephrosis; Hypertension; Kidney; Kidney Cortex; Kidney Medulla; Ligation; Rats; Rodent Diseases; Transplantation, Homologous; Ureter
PubMed: 998730
DOI: No ID Found -
International Journal of Molecular... Jun 2022Pregnancy is characterized by adaptations in the function of several maternal body systems that ensure the development of the fetus whilst maintaining health of the...
Pregnancy is characterized by adaptations in the function of several maternal body systems that ensure the development of the fetus whilst maintaining health of the mother. The renal system is responsible for water and electrolyte balance, as well as waste removal. Thus, it is imperative that structural and functional changes occur in the kidney during pregnancy. However, our knowledge of the precise morphological and molecular mechanisms occurring in the kidney during pregnancy is still very limited. Here, we investigated the changes occurring in the mouse kidney during pregnancy by performing an integrated analysis involving histology, gene and protein expression assays, mass spectrometry profiling and bioinformatics. Data from non-pregnant and pregnant mice were used to identify critical signalling pathways mediating changes in the maternal kidneys. We observed an expansion of renal medulla due to proliferation and infiltration of interstitial cellular constituents, as well as alterations in the activity of key cellular signalling pathways (e.g., AKT, AMPK and MAPKs) and genes involved in cell growth/metabolism (e.g., and ) in the kidneys during pregnancy. We also generated plasma and urine proteomic profiles, identifying unique proteins in pregnancy. These proteins could be used to monitor and study potential mechanisms of renal adaptations during pregnancy and disease.
Topics: Animals; Female; Fetus; Kidney; Kidney Medulla; Mice; Pregnancy; Proteins; Proteomics; Water-Electrolyte Balance
PubMed: 35682969
DOI: 10.3390/ijms23116287 -
Locations, abundances, and possible functions of FXYD ion transport regulators in rat renal medulla.American Journal of Physiology. Renal... Nov 2006The gamma-subunit of Na-K-ATPase (FXYD2) and corticosteroid hormone-induced factor (CHIF; FXYD4) are considered pump regulators in kidney tubules. The aim of this study...
The gamma-subunit of Na-K-ATPase (FXYD2) and corticosteroid hormone-induced factor (CHIF; FXYD4) are considered pump regulators in kidney tubules. The aim of this study was to expand the information about their locations in the kidney medulla and to evaluate their importance for electrolyte excretion in an animal model. The cellular and subcellular locations and abundances of gamma and CHIF in the medulla of control and sodium-depleted rats were analyzed by immunofluorescence and immunoelectron microscopy and semiquantitative Western blotting. The results showed that antibodies against the gamma-subunit COOH terminus and splice variant gamma(a), but not splice variant gamma(b), labeled intercalated cells, but not principal cells, in the initial part of the inner medullary collecting duct (IMCD1). In subsequent segments (IMCD2 and IMCD3), all principal cells exhibited distinct basolateral labeling for both the gamma-subunit COOH terminus, splice variant gamma(a), and CHIF. Splice variant gamma(b) was abundant in the inner stripe of the outer medulla but absent in the inner medulla (IM). Double labeling by high-resolution immunoelectron microscopy showed close structural association between CHIF and the Na-K-ATPase alpha(1)-subunit in basolateral membranes. The present observations provide new information about the cellular and subcellular locations of gamma and CHIF in the renal medulla and show a new gamma variant in the IM. Extensive NaCl depletion did not induce significant changes in the locations or abundances of the gamma-subunit COOH terminus and CHIF in different kidney zones. We conclude that the unchanged levels of these two FXYD proteins suggest that they are not primary determinants for urine electrolyte composition during NaCl depletion.
Topics: Animals; Diet, Sodium-Restricted; Fluorescent Antibody Technique; Intracellular Signaling Peptides and Proteins; Kidney Medulla; Male; Microscopy, Immunoelectron; Potassium Channels; Rats; Rats, Wistar; Sodium Chloride; Sodium-Potassium-Exchanging ATPase
PubMed: 16757733
DOI: 10.1152/ajprenal.00086.2006 -
BMJ Case Reports Nov 2014Actinomycosis of the kidney is rare and less than 50 cases have been reported in the English literature. Reported presentations are pyelonephritis, renal abscesses or...
Actinomycosis of the kidney is rare and less than 50 cases have been reported in the English literature. Reported presentations are pyelonephritis, renal abscesses or pyonephrosis. To date, one case of actinomycosis associated necrotising papillitis has been reported. We describe the second case of such a rare association of actinomycosis with papillary necrosis.
Topics: Actinomyces; Actinomycosis; Humans; Inflammation; Kidney; Kidney Medulla; Kidney Papillary Necrosis; Male; Middle Aged
PubMed: 25406215
DOI: 10.1136/bcr-2014-205892 -
American Journal of Physiology. Renal... Dec 2018The renal medulla is prone to hypoxia. Medullary hypoxia is postulated to be a leading cause of acute kidney injury, so there is considerable interest in predicting the...
The renal medulla is prone to hypoxia. Medullary hypoxia is postulated to be a leading cause of acute kidney injury, so there is considerable interest in predicting the oxygen tension in the medulla. Therefore we have developed a computational model for blood and oxygen transport within a physiologically normal rat renal medulla, using a multilevel modeling approach. For the top-level model we use the theory of porous media and advection-dispersion transport through a realistic three-dimensional representation of the medulla's gross anatomy to describe blood flow and oxygen transport throughout the renal medulla. For the lower-level models, we employ two-dimensional reaction-diffusion models describing the distribution of oxygen through tissue surrounding the vasculature. Steady-state model predictions at the two levels are satisfied simultaneously, through iteration between the levels. The computational model was validated by simulating eight sets of experimental data regarding renal oxygenation in rats (using 4 sets of control groups and 4 sets of treatment groups, described in 4 independent publications). Predicted medullary tissue oxygen tension or microvascular oxygen tension for control groups and for treatment groups that underwent moderate perturbation in hemodynamic and renal functions is within ±2 SE values observed experimentally. Diffusive shunting between descending and ascending vasa recta is predicted to be only 3% of the oxygen delivered. The validation tests confirm that the computational model is robust and capable of capturing the behavior of renal medullary oxygenation in both normal and early-stage pathological states in the rat.
Topics: Acute Kidney Injury; Animals; Biological Transport; Cell Hypoxia; Cellular Microenvironment; Computer Simulation; Diffusion; Kidney Medulla; Models, Biological; Oxygen; Rats; Renal Circulation; Reproducibility of Results
PubMed: 30256129
DOI: 10.1152/ajprenal.00363.2018 -
American Journal of Physiology.... Apr 2013Comparative studies of renal structure and function have potential to provide insights into the urine-concentrating mechanism of the mammalian kidney. This review... (Review)
Review
Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla.
Comparative studies of renal structure and function have potential to provide insights into the urine-concentrating mechanism of the mammalian kidney. This review focuses on the tubular transport pathways for water and urea that play key roles in fluid and solute movements between various compartments of the rodent renal inner medulla. Information on aquaporin water channel and urea transporter expression has increased our understanding of functional segmentation of medullary thin limbs of Henle's loops, collecting ducts, and vasa recta. A more complete understanding of membrane transporters and medullary architecture has identified new and potentially significant interactions between these structures and the interstitium. These interactions are now being introduced into our concept of how the inner medullary urine-concentrating mechanism works. A variety of regulatory pathways lead directly or indirectly to variable patterns of fluid and solute movements among the interstitial and tissue compartments. Animals with the ability to produce highly concentrated urine, such as desert species, are considered to exemplify tubular structure and function that optimize urine concentration. These species may provide unique insights into the urine-concentrating process.(1)
Topics: Animals; Biological Transport; Kidney Medulla; Nephrons; Rodentia; Urea; Water
PubMed: 23364530
DOI: 10.1152/ajpregu.00456.2012 -
American Journal of Physiology.... Aug 2019In experimental sepsis, the rapid development of renal medullary hypoxia precedes the development of acute kidney injury (AKI) and may contribute to its pathogenesis. We...
In experimental sepsis, the rapid development of renal medullary hypoxia precedes the development of acute kidney injury (AKI) and may contribute to its pathogenesis. We investigated whether inhibiting active sodium transport and oxygen consumption in the medullary thick ascending limb with furosemide attenuates the medullary hypoxia in experimental septic AKI. Sheep were instrumented with flow probes on the pulmonary and renal arteries and fiber optic probes to measure renal cortical and medullary perfusion and oxygen tension (Po). Sepsis and AKI were induced by infusion of live . At 24 h of sepsis there were significant decreases in renal medullary tissue perfusion (1,332 ± 233 to 698 ± 159 blood perfusion units) and Po (44 ± 6 to 19 ± 6 mmHg) (both < 0.05). By 5 min after intravenous administration of furosemide (20 mg), renal medullary Po increased to 43 ± 6 mmHg and remained at this normal level for 8 h. Furosemide caused transient increases in fractional excretion of sodium and creatinine clearance, but medullary perfusion, renal blood flow, and renal oxygen delivery were unchanged. Urinary F-isoprostanes, an index of oxidative stress, were not significantly changed at 24 h of sepsis but tended to transiently decrease after furosemide treatment. In septic AKI, furosemide rapidly restored medullary Po to preseptic levels. This effect was not accompanied by changes in medullary perfusion or renal oxygen delivery but was accompanied by a transient increase in fractional sodium excretion, implying decreased oxygen consumption as a mechanism.
Topics: Acute Kidney Injury; Animals; Furosemide; Hypoxia; Kidney; Kidney Function Tests; Kidney Medulla; Oxygen Consumption; Renal Circulation; Sheep
PubMed: 31141418
DOI: 10.1152/ajpregu.00371.2018