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PloS One 2016Renal tubulointerstitial injury often leads to interstitial fibrosis and tubular atrophy (IF/TA). IF/TA is typically assessed in the renal cortex and can be objectively...
Renal tubulointerstitial injury often leads to interstitial fibrosis and tubular atrophy (IF/TA). IF/TA is typically assessed in the renal cortex and can be objectively quantitated with computerized image analysis (IA). However, the human medulla accounts for a substantial proportion of the nephron; therefore, medullary scarring will have important cortical consequences and may parallel overall chronic renal injury. Trichrome, periodic acid-Schiff (PAS), and collagen III immunohistochemistry (IHC) were visually examined and quantitated on scanned whole slide images (WSIs) (N = 67 cases). When tuned to measure fibrosis, IA of trichrome and Trichrome-PAS (T-P) WSIs correlated for all anatomic compartments (among cortex, medulla, and entire tissue, r = 0.84 to 0.89, P all <0.0001); and collagen III deposition correlated between compartments (r = 0.69 to 0.89, P <0.0001 to 0.0002); however, trichrome and T-P measures did not correlate with collagen deposition, suggesting heterogeneous contributions to extracellular matrix deposition. Epithelial cell mass (EPCM) correlated between cortex and medulla when measured with cytokeratin IHC and with the trichrome red portion (r = 0.85 and 0.66, respectively, all P < 0.0001). Visual assessment also correlated between compartments for fibrosis and EPCM. Correlations were found between increasing medullary inner stripe (IS) width and fibrosis in all of the tissue and the medulla by trichrome morphometry (r = 0.56, P < 0.0001, and r = 0.48, P = 0.00008, respectively). Weak correlations were found between increasing IS width and decreasing visual assessment of all tissue EPCM. Microvessel density (MVD) and microvessel area (MVA) measured using a MVD algorithm applied to CD34 IHC correlated significantly between all compartments (r = 0.76 to 0.87 for MVD and 0.71 to 0.87 for MVA, P all < 0.0001). Overall, these findings demonstrate the interrelatedness of the cortex and medulla and the importance of considering the renal parenchyma as a whole.
Topics: Algorithms; Collagen; Fibrosis; Humans; Image Processing, Computer-Assisted; Kidney Cortex; Kidney Function Tests; Kidney Medulla; Microvessels
PubMed: 27575381
DOI: 10.1371/journal.pone.0161019 -
Genomics May 2020Camels as a sort of animal long living in desert have evolved stress-resistance characteristics to adapt to environment with high temperature and water shortage...
Camels as a sort of animal long living in desert have evolved stress-resistance characteristics to adapt to environment with high temperature and water shortage environment. However, the research of non-coding RNA (ncRNA)-mediated molecular regulation about how camel responds to arid condition in post-transcriptional regulation level is deficient. Under water-deprivation stress, by RNA-sequencing of camel renal medulla associated with regulating water metabolism, we detected significantly differential 575 alternative splicing events (ASEs) and 17 mRNAs, 26 miRNAs and 0 lncRNA. The down-regulated ACLY and LOC105061856, up-regulated PCBP2 and miR-195 potentially targeting LOC105061856 and PCBP2 mRNA were selected as candidate resistance-related genes. In quantitative experiment, the expression level of above four genes was consistent with RNA-seq data by qRT-PCR. The suppressive cell dehydration with down-regulated ACLY, inhibitive aerobic respiration with down-regulated LOC105061856 targeted by miR-195 and strong anti-oxidative capability with PCBP2 aimed by miR-195 may be regulatory modes of camel renal medulla adapting to water-deprivation condition.
Topics: Alternative Splicing; Animals; Camelus; Dehydration; Droughts; Female; Gene Expression Regulation; Kidney Medulla; MicroRNAs; RNA, Long Noncoding; RNA, Messenger
PubMed: 32070763
DOI: 10.1016/j.ygeno.2020.02.014 -
American Journal of Physiology. Renal... Feb 2015The physiological evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to... (Review)
Review
The physiological evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to regulation of medullary blood flow, sodium homeostasis, and long-term control of blood pressure is summarized in this review. Data obtained largely from rats indicate that experimentally induced elevations of either superoxide or hydrogen peroxide in the renal medulla result in reduction of medullary blood flow, enhanced Na(+) reabsorption, and hypertension. A shift in the redox balance between nitric oxide and reactive oxygen species (ROS) is found to occur naturally in the Dahl salt-sensitive (SS) rat model, where selective reduction of ROS production in the renal medulla reduces salt-induced hypertension. Excess medullary production of ROS in SS rats emanates from the medullary thick ascending limbs of Henle [from both the mitochondria and membrane NAD(P)H oxidases] in response to increased delivery and reabsorption of excess sodium and water. There is evidence that ROS and perhaps other mediators such as ATP diffuse from the mTAL to surrounding vasa recta capillaries, resulting in medullary ischemia, which thereby contributes to hypertension.
Topics: Animals; Humans; Hypotension; Kidney Medulla; NADPH Oxidases; Nitric Oxide; Reactive Oxygen Species; Sodium
PubMed: 25354941
DOI: 10.1152/ajprenal.00455.2014 -
FASEB Journal : Official Publication of... Jan 2019Increasing evidence supports the important role of HS in renal physiology and the pathogenesis of kidney injury. Whether HS regulates water metabolism in the kidney and...
Increasing evidence supports the important role of HS in renal physiology and the pathogenesis of kidney injury. Whether HS regulates water metabolism in the kidney and the potential mechanism are still unknown. The present study was conducted to determine the role of HS in urine concentration. Inhibition of both cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), 2 major enzymes for endogenous HS production, with propargylglycine (PPG) and amino-oxyacetate (AOAA), respectively, caused increased urine output and reduced urine osmolality in mice that was associated with decreased expression of aquaporin (AQP)-2 in the renal inner medulla. Mice treated with both PPG and AOAA developed a urine concentration defect in response to dehydration that was accompanied by reduced AQP-2 protein expression. Inhibition of CSE alone was associated with a mild decrease in AQP-2 protein level in the renal medulla of heterozygous CBS mice. GYY4137, a slow HS donor, markedly improved urine concentration and prevented the down-regulation of renal AQP-2 protein expression in mice with lithium-induced nephrogenic diabetes insipidus (NDI). GYY4137 significantly increased cAMP levels in cell lysates prepared from inner medullary collecting duct (IMCD) suspensions. AQP-2 protein expression was also upregulated, but was significantly inhibited by the adenyl cyclase inhibitor MDL12330A or the PKA inhibitor H89, but not the vasopressin 2 receptor (VR) antagonist tolvaptan. Inhibition of endogenous HS production impaired urine concentration in mice, whereas an exogenous HS donor improved urine concentration in lithium-induced NDI by increasing AQP-2 expression in the collecting duct principal cells. HS upregulated AQP-2 protein expression, probably via the cAMP-PKA pathway.-Luo, R., Hu, S., Liu, Q., Han, M., Wang, F., Qiu, M., Li, S., Li, X., Yang, T., Fu, X., Wang, W., Li, C. Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.
Topics: Alkynes; Aminooxyacetic Acid; Animals; Aquaporin 2; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Gasotransmitters; Glycine; Hydrogen Sulfide; Kidney Medulla; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Urinalysis; Urination; Urine
PubMed: 30036087
DOI: 10.1096/fj.201800436R -
American Journal of Physiology. Renal... May 2015The goal of this study was to investigate the reciprocal interactions among oxygen (O2), nitric oxide (NO), and superoxide (O2 (-)) and their effects on medullary...
The goal of this study was to investigate the reciprocal interactions among oxygen (O2), nitric oxide (NO), and superoxide (O2 (-)) and their effects on medullary oxygenation and urinary output. To accomplish that goal, we developed a detailed mathematical model of solute transport in the renal medulla of the rat kidney. The model represents the radial organization of the renal tubules and vessels, which centers around the vascular bundles in the outer medulla and around clusters of collecting ducts in the inner medulla. Model simulations yield significant radial gradients in interstitial fluid oxygen tension (Po2) and NO and O2 (-) concentration in the OM and upper IM. In the deep inner medulla, interstitial fluid concentrations become much more homogeneous, as the radial organization of tubules and vessels is not distinguishable. The model further predicts that due to the nonlinear interactions among O2, NO, and O2 (-), the effects of NO and O2 (-) on sodium transport, osmolality, and medullary oxygenation cannot be gleaned by considering each solute's effect in isolation. An additional simulation suggests that a sufficiently large reduction in tubular transport efficiency may be the key contributing factor, more so than oxidative stress alone, to hypertension-induced medullary hypoxia. Moreover, model predictions suggest that urine Po2 could serve as a biomarker for medullary hypoxia and a predictor of the risk for hospital-acquired acute kidney injury.
Topics: Acute Kidney Injury; Animals; Biological Transport; Cell Hypoxia; Computer Simulation; Hypertension; Kidney Concentrating Ability; Kidney Medulla; Kidney Tubules; Models, Biological; Nitric Oxide; Nonlinear Dynamics; Oxidative Stress; Oxygen; Rats; Renal Circulation; Sodium; Superoxides
PubMed: 25651567
DOI: 10.1152/ajprenal.00600.2014 -
Kidney International. Supplement Sep 1998Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently... (Review)
Review
Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently unknown. Using electron microscopic autoradiography, we have mapped the receptors for angiotensin II (Ang II [AT1 and AT2]), endothelin (ET(A) and ET(B)), and bradykinin (B2) in the rat renal medulla. Although these peptide receptors show distinct vascular and tubular distributions, they overlap strikingly in renomedullary interstitial cells (RMICs) of the inner stripe and the papilla. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis, mRNAs for AT1A, ET(A), and B2 receptors were detected in cultured adult RMICs. Ang II increases intracellular inositol 1,4,5-triphosphate (IP3) and [Ca2+]i and stimulates [3H]thymidine incorporation and extracellular matrix (ECM) synthesis via AT1A receptors. Endothelin and bradykinin also stimulate cell proliferation and ECM synthesis in RMICs through ET(A) and B2 receptors, respectively, but the actions of endothelin are modulated by concurrent nitric oxide production. By contrast, AT2 receptor mRNA was detected only in embryonic RMICs, in which Ang II inhibits cell proliferation through this receptor. These results suggest that multiple vasoactive peptides may interact with RMICs to exert endocrine and/or paracrine influences on renal medullary microcirculation and tubular function.
Topics: Animals; Kidney Medulla; Receptor, Bradykinin B2; Receptors, Angiotensin; Receptors, Bradykinin; Receptors, Endothelin
PubMed: 9736248
DOI: 10.1046/j.1523-1755.1998.06705.x -
American Journal of Physiology.... Jan 2014We describe the determinants of urinary oxygen tension (Po2) and the potential for use of urinary PO2 as a "physiological biomarker" of the risk of acute kidney injury... (Review)
Review
We describe the determinants of urinary oxygen tension (Po2) and the potential for use of urinary PO2 as a "physiological biomarker" of the risk of acute kidney injury (AKI) in hospital settings. We also identify knowledge gaps required for clinical translation of bedside monitoring of urinary PO2. Hypoxia in the renal medulla is a hallmark of AKI of diverse etiology. Urine in the collecting ducts would be expected to equilibrate with the tissue PO2 of the inner medulla. Accordingly, the PO2 of urine in the renal pelvis changes in response to stimuli that would be expected to alter oxygenation of the renal medulla. Oxygen exchange across the walls of the ureter and bladder will confound measurement of the PO2 of bladder urine. Nevertheless, the PO2 of bladder urine also changes in response to stimuli that would be expected to alter renal medullary oxygenation. If confounding influences can be understood, urinary bladder PO2 may provide prognostically useful information, including for prediction of AKI after cardiopulmonary bypass surgery. To translate bedside monitoring of urinary PO2 into the clinical setting, we require 1) a more detailed knowledge of the relationship between renal medullary oxygenation and the PO2 of pelvic urine under physiological and pathophysiological conditions; 2) a quantitative understanding of the impact of oxygen transport across the ureteric epithelium on urinary PO2 measured from the bladder; and 3) a simple, robust medical device that can be introduced into the bladder via a standard catheter to provide reliable and continuous measurement of urinary PO2.
Topics: Acute Kidney Injury; Animals; Blood Gas Analysis; Humans; Hypoxia; Kidney Medulla; Oxygen; Urinary Bladder
PubMed: 24226029
DOI: 10.1152/ajpregu.00437.2013 -
Mathematical Biosciences Jul 2017The metabolism of glucose provides most of the ATP required for energy-dependent transport processes. In the inner medulla of the mammalian kidney, limited blood flow...
The metabolism of glucose provides most of the ATP required for energy-dependent transport processes. In the inner medulla of the mammalian kidney, limited blood flow and O supply yield low oxygen tension; therefore, a substantial fraction of the glucose metabolism in that region is anaerobic. Lactate is considered to be a waste product of anaerobic glycolysis, which yields two lactate molecules for each glucose molecule consumed, thereby likely leading to the production and accumulation of a significant amount of lactate in the inner medulla. To gain insights into the transport and metabolic processes in the kidney, we have developed a detailed mathematical model of the renal medulla of the rat kidney. The model represents the radial organization of the renal tubules and vessels, which centers around the vascular bundles in the outer medulla and around clusters of collecting ducts in the inner medulla. Model simulations yield significant radial gradients in interstitial fluid oxygen tension and glucose and lactate concentrations in the outer medulla and upper inner medulla. In the deep inner medulla, interstitial fluid concentrations become much more homogeneous, as the radial organization of tubules and vessels is not distinguishable. Using this model, we have identified parameters concerning glucose transport and basal metabolism, as well as lactate production via anaerobic glycolysis, that yield predicted blood glucose and lactate concentrations consistent with experimental measurements in the papillary tip. In addition, simulations indicate that the radial organization of the rat kidney may affect lactate buildup in the inner medulla.
Topics: Adenosine Triphosphate; Animals; Computer Simulation; Glucose; Kidney; Kidney Medulla; Kidney Tubules; Lactic Acid; Models, Biological; Rats
PubMed: 28495544
DOI: 10.1016/j.mbs.2017.04.008 -
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 -
The Journal of Pharmacology and... Sep 2012Medullipin has been proposed to be an antihypertensive lipid hormone released from the renal medulla in response to increased arterial pressure and renal medullary blood...
Medullipin has been proposed to be an antihypertensive lipid hormone released from the renal medulla in response to increased arterial pressure and renal medullary blood flow. Because anandamide (AEA) possesses characteristics of this purported hormone, the present study tested the hypothesis that AEA or one of its metabolites represents medullipin. AEA was demonstrated to be enriched in the kidney medulla compared with cortex. Western blotting and enzymatic analyses of renal cortical and medullary microsomes revealed opposite patterns of enrichment of two AEA-metabolizing enzymes, with fatty acid amide hydrolase higher in the renal cortex and cyclooxygenase-2 (COX-2) higher in the renal medulla. In COX-2 reactions with renal medullary microsomes, prostamide E2, the ethanolamide of prostaglandin E₂, was the major product detected. Intramedullarily infused AEA dose-dependently increased urine volume and sodium and potassium excretion (15-60 nmol/kg/min) but had little effect on mean arterial pressure (MAP). The renal excretory effects of AEA were blocked by intravenous infusion of celecoxib (0.1 μg/kg/min), a selective COX-2 inhibitor, suggesting the involvement of a prostamide intermediate. Plasma kinetic analysis revealed longer elimination half-lives for AEA and prostamide E2 compared with prostaglandin E₂. Intravenous prostamide E2 reduced MAP and increased renal blood flow (RBF), actions opposite to those of angiotensin II. Coinfusion of prostamide E2 inhibited angiotensin II effects on MAP and RBF. These results suggest that AEA and/or its prostamide metabolites in the renal medulla may represent medullipin and function as a regulator of body fluid and MAP.
Topics: Angiotensin II; Animals; Arachidonic Acids; Arterial Pressure; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Endocannabinoids; Glycerides; Kidney Cortex; Kidney Medulla; Kinetics; Lipids; Male; Mice; Mice, Inbred C57BL; Microsomes; Polyunsaturated Alkamides; Potassium; Pyrazoles; Renal Circulation; Sodium; Sulfonamides
PubMed: 22685343
DOI: 10.1124/jpet.112.196451