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The Journal of Pharmacology and... Jan 2021The G protein-coupled estrogen receptor 1 (GPER1) mediates rapid estrogenic signaling. We recently reported that activation of GPER1 in the renal medulla evokes...
The G protein-coupled estrogen receptor 1 (GPER1) mediates rapid estrogenic signaling. We recently reported that activation of GPER1 in the renal medulla evokes endothelin-1-dependent natriuresis in female, but not male, rats. However, the involvement of the ET receptors, ET and ET, underlying GPER1 natriuretic action remain unclear. In this study, we used genetic and pharmacologic methods to identify the contributions of ET and ET in mediating this female-specific natriuretic effect of renal medullary GPER1. Infusion of the GPER1-selective agonist G1 (5 pmol/kg per minute) into the renal medulla for 40 minutes increased Na excretion and urine flow in anesthetized female ET-deficient (ET def) rats and littermate controls but did not affect blood pressure or urinary K excretion in either group. Pretreatment with the selective ET inhibitor ABT-627 (5 mg/kg, intravenous) abolished G1-induced natriuresis in ET def rats. To further isolate the effects of inhibiting either receptor alone, we conducted the same experiments in anesthetized female Sprague-Dawley (SD) rats pretreated or not with ABT-627 and/or the selective ET inhibitor A-192621 (10 mg/kg, intravenous). Neither antagonism of ET nor antagonism of ET receptor alone affected the G1-induced increase in Na excretion and urine flow in SD rats. However, simultaneous antagonism of both receptors completely abolished these effects. These data suggest that ET and ET receptors can mediate the natriuretic and diuretic response to renal medullary GPER1 activation in female rats. SIGNIFICANCE STATEMENT: Activation of G protein-coupled estrogen receptor 1 (GPER1) in the renal medulla of female rats evokes natriuresis via endothelin receptors A and/or B, suggesting that GPER1 and endothelin signaling pathways help efficient sodium excretion in females. Thus, GPER1 activation could be potentially useful to mitigate salt sensitivity in females.
Topics: Animals; Atrasentan; Endothelin Receptor Antagonists; Female; Kidney Medulla; Natriuresis; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, G-Protein-Coupled
PubMed: 33127751
DOI: 10.1124/jpet.120.000322 -
PloS One 2019We recently provided highly suggestive preliminary evidence that the renal interstitium contracts reactively in vivo. We demonstrated that renal medullary direct...
We recently provided highly suggestive preliminary evidence that the renal interstitium contracts reactively in vivo. We demonstrated that renal medullary direct interstitial volume expansion (rmDIVE = 100 μl bolus infusion of 0.9% saline (SS)/30 s) brought about a biphasic renal interstitial hydrostatic pressure (RIHP) response which was abolished when dibutyryl-cAMP was concomitant and interstitially infused. To assess more deeply the feasibility of the concept that the renal interstitium contracts in vivo, two experimental series (S1, S2) were performed in hydropenic rats subjected to acute left renal-denervation, hormonal clamping, and control of renal arterial pressure. In S1, RIHP and renal outer medullary blood flow (RoMBF) were continuously measured before and after a sudden micro-bolus (5μl) injection, into the renal medullary interstitium, of SS containing α-trinositol (α-TNS, anti-inflammatory drug) to either two doses 2 or 4 mM (SS + 2 α-TNS and SS + 4 α-TNS groups). No overall differences between groups in either ΔRIHP or %ΔRoMBF time courses were found; however, in the SS + 2 α-TNS group the data were less scattered and the ΔRIHP time course tended to peak faster and then persisted there, so that, this α-TNS dose was selected for S2. In S2, RIHP and RoMBF were similarly measured in rats randomly assigned to three groups: the CTR group (sham time-control), SS group (SS alone), and SS + α-TNS group. The micro-bolus injection of SS alone (SS group) was unable to increase ΔRIHP. The group with no micro-bolus injection (CTR group) experienced a decrease in ΔRIHP. The micro-bolus injection of SS + 2 α-TNS was accompanied by a differential increase in ΔRIHP (vs. CTR and SS groups). These responses were not associated with differential changes among groups in %ΔRoMBF or hemodilution parameters. These results provide additional evidence that the renal interstitium contracts in vivo.
Topics: Animals; Hydrostatic Pressure; Kidney Medulla; Male; Rats; Rats, Wistar; Renal Circulation; Sodium Chloride; Vasoconstriction
PubMed: 31774858
DOI: 10.1371/journal.pone.0225640 -
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... Jan 2000Physiological and pharmacological studies have demonstrated that extracellular ATP, acting through P2Y(2) purinoceptor, modulates water permeability of renal medullary...
Physiological and pharmacological studies have demonstrated that extracellular ATP, acting through P2Y(2) purinoceptor, modulates water permeability of renal medullary collecting duct cells and the secretion of ions, mucin, and surfactant phospholipids by respiratory epithelia. Here we provide direct molecular evidence for the expression of P2Y(2) purinoceptor in these cells. RT-PCR confirmed P2Y(2) purinoceptor mRNA expression in rat lung and kidney and demonstrated expression in renal collecting ducts. Northern analysis showed that both lung and kidney express one 3.6-kb P2Y(2) purinoceptor mRNA transcript. Immunoblots using peptide-derived polyclonal antibody to P2Y(2) purinoceptor showed that inner medullary collecting ducts (IMCD) express two distinct and specific products (47 and 105 kDa) and account for the majority of the receptor expression in inner medulla, whereas the 105-kDa form is predominant in lung. Immunoperoxidase labeling on cryosections showed localization of receptor protein in the apical and basolateral domains of IMCD principal cells and in the secretory cells (Clara cells and goblet cells) of the terminal respiratory bronchioles.
Topics: Animals; Antibody Specificity; Blotting, Northern; Bronchi; Immunoblotting; Immunoenzyme Techniques; Immunohistochemistry; Kidney Medulla; Kidney Tubules, Collecting; Lung; Male; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2Y2; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 10644654
DOI: 10.1152/ajprenal.2000.278.1.F43 -
Kidney International Oct 1996The distinctive feature of the renal function and metabolism implicate a possibility of excessive ATP degradation during insufficient oxygen supply. Protection of the...
The distinctive feature of the renal function and metabolism implicate a possibility of excessive ATP degradation during insufficient oxygen supply. Protection of the purine ring against degradation is one among other functions of the purine nucleotide cycle (PNC). The purpose of this study was to estimate the activity of PNC in cytosol of rat renal cortex and medulla under conditions that mimic normal and low oxygen supply in vivo. In normoxic-like condition the rate of AMP deamination was 1.7 and 2.0 nmol/mg protein/min in the cytosol of cortex and medulla, respectively. Under this condition, the rate of IMP reamination was similar to that of AMP deamination. In a hypoxia-like condition the rate of AMP deamination increased by 41% in cytosol from both parts of the kidney, while the rate of IMP reamination remained unchanged in the cytosol of medulla and decreased by 46% in the cortex cytosol. Distribution of the other enzymes of the PNC, that is, adenylosuccinate synthetase and adenylosuccinate lyase, in the cytosol of cortex and medulla correlated with that observed for AMP deamination and IMP reamination potentials. At 150 microM IMP, the activity of adenylosuccinate synthetase in the cortex and medulla was 0.34 and 1.24 nmol/mg protein/min, respectively. Activity of the adenylosuccinate lyase was severalfold greater than the respective activity of the adenylosuccinate synthetase. These results show that the efficiency of PNC is about twice as high in the medulla cytosol as in the cortex cytosol, and that the activity of PNC in kidney is mainly limited by the activity of adenylosuccinate synthetase and supply of AMP.
Topics: Adenine Nucleotides; Adenylosuccinate Lyase; Adenylosuccinate Synthase; Amination; Ammonia; Animals; Coformycin; Deamination; Dose-Response Relationship, Drug; Hypoxia; Kidney Cortex; Kidney Medulla; Male; Purine Nucleotides; Rats; Rats, Wistar; Time Factors
PubMed: 8887278
DOI: 10.1038/ki.1996.428 -
American Journal of Physiology. Renal... Aug 2017We recently reported that natriuresis produced by renal medullary salt loading is dependent on endothelin (ET)-1 and purinergic (P2) receptors in male rats. Because sex...
We recently reported that natriuresis produced by renal medullary salt loading is dependent on endothelin (ET)-1 and purinergic (P2) receptors in male rats. Because sex differences in ET-1 and P2 signaling have been reported, we decided to test whether ovarian sex hormones regulate renal medullary ET-1 and P2-dependent natriuresis. The effect of medullary NaCl loading on Na excretion was determined in intact and ovariectomized (OVX) female Sprague-Dawley rats with and without ET-1 or P2 receptor antagonism. Isosmotic saline (284 mosmol/kgHO) was infused in the renal medullary interstitium of anesthetized rats during a baseline urine collection period, followed by isosmotic or hyperosmotic saline (1,800 mosmol/kgHO) infusion. Medullary NaCl loading significantly enhanced Na excretion in intact and OVX female rats. ET or P2 receptor blockade did not attenuate the natriuretic effect of medullary NaCl loading in intact females, whereas ET or P2 receptor blockade attenuated the natriuretic response to NaCl loading in OVX rats. Activation of medullary P2Y and P2Y receptors by UTP infusion had no significant effect in intact females but enhanced Na excretion in OVX rats. Combined ET receptor blockade significantly inhibited the natriuretic response to UTP observed in OVX rats. These data demonstrate that medullary NaCl loading induces ET-1 and P2-independent natriuresis in intact females. In OVX, activation of medullary P2 receptors promotes ET-dependent natriuresis, suggesting that ovarian hormones may regulate the interplay between the renal ET-1 and P2 signaling systems to facilitate Na excretion.
Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Female; Kidney Medulla; Natriuresis; Ovariectomy; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2Y2; Renal Elimination; Signal Transduction; Sodium; Sodium Chloride; Time Factors
PubMed: 28468962
DOI: 10.1152/ajprenal.00098.2017 -
Experimental Physiology May 2024It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the...
It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.
Topics: Animals; Furosemide; Acetazolamide; Amiloride; Diuretics; Sheep; Female; Kidney Cortex; Kidney Medulla; Oxygen; Hemodynamics; Oxygen Consumption
PubMed: 38551893
DOI: 10.1113/EP091479 -
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 -
Mathematical Medicine and Biology : a... Sep 2017Renal hypoxia could result from a mismatch in renal oxygen supply and demand, particularly in the renal medulla. Medullary hypoxic damage is believed to give rise to...
Renal hypoxia could result from a mismatch in renal oxygen supply and demand, particularly in the renal medulla. Medullary hypoxic damage is believed to give rise to acute kidney injury, which is a prevalent complication of cardiac surgery performed on cardiopulmonary bypass (CPB). To determine the mechanisms that could lead to medullary hypoxia during CPB in the rat kidney, we developed a mathematical model which incorporates (i) autoregulation of renal blood flow and glomerular filtration rate, (ii) detailed oxygen transport and utilization in the renal medulla and (iii) oxygen transport along the ureter. Within the outer medulla, the lowest interstitial tissue P$_{\rm O2}$, which is an indicator of renal hypoxia, is predicted near the thick ascending limbs. Interstitial tissue P$_{\rm O2}$ exhibits a general decrease along the inner medullary axis, but urine P$_{\rm O2}$ increases significantly along the ureter. Thus, bladder urinary P$_{\rm O2}$ is predicted to be substantially higher than medullary P$_{\rm O2}$. The model is used to identify the phase of cardiac surgery performed on CPB that is associated with the highest risk for hypoxic kidney injury. Simulation results indicate that the outer medulla's vulnerability to hypoxic injury depends, in part, on the extent to which medullary blood flow is autoregulated. With imperfect medullary blood flow autoregulation, the model predicts that the rewarming phase of CPB, in which medullary blood flow is low but medullary oxygen consumption remains high, is the phase in which the kidney is most likely to suffer hypoxic injury.
Topics: Animals; Cardiopulmonary Bypass; Computer Simulation; Homeostasis; Hypothermia, Induced; Hypoxia; Kidney Medulla; Mathematical Concepts; Models, Animal; Models, Biological; Oxygen; Oxygen Consumption; Rats; Renal Circulation; Ureter
PubMed: 27281792
DOI: 10.1093/imammb/dqw010 -
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