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Hypertension (Dallas, Tex. : 1979) Nov 2008
Review
Topics: Animals; Homeostasis; Humans; Hypertension; Kidney Medulla; Natriuresis; Nitric Oxide; Oxidative Stress; Oxygen; Rats; Sodium
PubMed: 18852392
DOI: 10.1161/HYPERTENSIONAHA.107.092858 -
Hypertension Research : Official... Dec 1997The renal medulla plays an important role in maintaining body fluid and electrolyte balance and long-term blood pressure homeostasis through its unique structural and... (Review)
Review
The renal medulla plays an important role in maintaining body fluid and electrolyte balance and long-term blood pressure homeostasis through its unique structural and functional properties. Among several humoral, paracrine factors or autocoids, angiotensin II (Ang II) has been implicated in the regulation of renal medullary function, including the medullary/papillary microcirculation, urine concentration, and blood pressure, but the mechanisms by which Ang II exerts influences in the renal medulla are largely unknown. The purpose of this review is to summarize the cellular localization, regulation, and functional properties of Ang II AT1 receptors in the kidney, with special emphasis on type I renomedullary interstitial cells (RMICs) in the renal medulla and cultured RMICs. High densities of AT1 receptors have been localized in type I RMICs in the inner stripe of the outer medulla by high resolution light and electron microscopic autoradiography following in vitro or in vivo labelling, or in cultured RMICs. Furthermore, reverse transcription polymerase chain reaction and Southern blot analysis now confirm that AT1 receptors in cultured RMICs are exclusively of the AT1A subtype. In cultured RMICs, Ang II markedly increases intracellular inositol 1,4,5-triphosphate (IP3) concentration, and stimulates cell proliferation and extracellular matrix synthesis, and these cellular responses are exclusively mediated by AT1 receptors. Considering the co-occurrence of high levels of renin, renin substrate angiotensinogen, and Ang II in the interstitial fluid compartment, and AT1 receptors in type I RMICs of the renal medulla, the AT1 receptor-bearing RMICs may be more responsive to the locally formed interstitial Ang II than to the circulating peptide. Since RMICs also contain the receptors for other vasoactive peptides, such as endothelin (ET[A] and ET[B]), natriuretic peptides (NPR[A] and NPR[B]), and bradykinin (B2), and synthesize prostaglandins and medullipins, they may serve as an important site for functional interactions between Ang II and other vasoactive peptides in modulating renal medullary function. More studies using different experimental approaches are therefore required to explore and elucidate the functional role of renal interstitial Ang II and AT1 receptors in RMICs in the physiological control of renal medullary function and in the pathophysiology of hypertension and progressive renal diseases.
Topics: Connective Tissue Cells; Humans; Kidney; Kidney Medulla; Male; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin
PubMed: 9453258
DOI: 10.1291/hypres.20.233 -
Kidney International Jun 2019Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary...
Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated at a pump flow of 80 mL kgmin and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kgmin, while MAP was maintained at approximately 70 mm Hg. MAP was then increased by vasopressor (metaraminol, 0.2-0.6 mg/min) infusion at a pump flow of 80 mL kgmin. CPB at 80 mL kgmin reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary Po from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kgmin further decreased RBF (-16%) and medullary Po from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kgmin increased RBF (17%) and medullary Po from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary Po from 19 to 39 mm Hg. Thus, the renal medulla is susceptible to hypoxia during CPB, but medullary oxygenation can be improved by increasing pump flow or increasing target MAP by infusion of metaraminol.
Topics: Acute Kidney Injury; Animals; Arterial Pressure; Cardiopulmonary Bypass; Cell Hypoxia; Disease Models, Animal; Female; Humans; Kidney Medulla; Metaraminol; Oxygen; Postoperative Complications; Renal Circulation; Sheep; Vasoconstrictor Agents
PubMed: 31005272
DOI: 10.1016/j.kint.2019.01.032 -
American Journal of Physiology. Renal... Mar 2014
Topics: Animals; Kidney Medulla; Male
PubMed: 24370589
DOI: 10.1152/ajprenal.00663.2013 -
Kidney International Mar 1997Radiocontrast agents and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the diagnosis and treatment of renal colic. We studied their impact during...
Radiocontrast agents and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the diagnosis and treatment of renal colic. We studied their impact during unilateral acute urinary outflow obstruction upon renal microcirculation and parenchymal integrity. Laser-Doppler and ultrasonic regional flow measurements demonstrated selective decline of outer medullary blood flow by 23 +/- 2% during an acute increase of intra-pelvic pressure to 50 to 55 cm H2O (N = 28, X +/- SEM, P < 0.01). In rats preconditioned with indomethacin, this manipulation reduced medullary blood flow by 50 +/- 4% (N = 16, P < 0.01 vs. obstruction alone), with cortical and total renal blood flow declining by 18 +/- 4% and 16 +/- 2%, respectively (P < 0.01). Unilateral obstruction alone for 24 hours in intact rats resulted in injury (hemorrhage and necrosis) to the papilla and fornix (formed laterally by inner stripe and medially by the inner medulla). These changes were detected as early as 30 minutes after ureteral ligature by staining for fragmented nuclear DNA (TUNEL). Mild damage of thick ascending limbs (mTALs) was associated with substantial medial fornix injury. Indomethacin markedly increased mTAL injury in obstructed kidneys, but attenuated inner medullary damage, both in the medial border of the urinary space and at the papilla. This latter protective effect, probably mediated by the decrease in intrapelvic pressure, was blunted by concomitant intravenous fluid load. Contrast media (iothalamate) and L-NAME (N omega nitro-L-arginine methyl ester) both augmented inner stripe and inner medullary damage in hydronephrotic kidneys. In rats concomitantly subjected to radiocontrast, indomethacin and L-NAME (an acute renal failure protocol, J Clin Invest 94:1069, 1994), unilateral obstruction augmented inner stripe hypoxic damage (65 +/- 6% vs. 24 +/- 11% of mTALs in contralateral kidneys, N = 7, P < 0.01). Injury was maximal at the fornix (93 +/- 6% vs. 39 +/- 14% of mTALs in the mid-inner stripe, P < 0.01) and extended to the outer stripe and medullary rays. Thus, in the rat acute ureteral obstruction alters medullary blood flow and within 24 hours produces medullary damage in both forniceal and inner medullary locations, that is exacerbated by concomitant measures which limit medullary oxygenation. Contrast studies, forced hydration and NSAIDs for renal colic are potentially harmful and their use should be re-evaluated.
Topics: Acute Disease; Animals; Contrast Media; DNA Fragmentation; Hypoxia; Indomethacin; Iothalamic Acid; Kidney Medulla; Male; Microcirculation; Microscopy, Electron; NG-Nitroarginine Methyl Ester; Rats; Rats, Sprague-Dawley; Renal Circulation; Sodium Chloride; Ureteral Obstruction
PubMed: 9067896
DOI: 10.1038/ki.1997.95 -
The Journal of Clinical Investigation Apr 2010Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal...
Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1+/- mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress-induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1+/- mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.
Topics: Animals; Apoptosis; Cells, Cultured; Cyclooxygenase 2; Fibrosis; Heterocyclic Compounds, 4 or More Rings; Kidney Medulla; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Resveratrol; Sirtuin 1; Stilbenes; Ureteral Obstruction
PubMed: 20335659
DOI: 10.1172/JCI41563 -
American Journal of Physiology. Renal... Aug 2014We have developed a highly detailed mathematical model of solute transport in the renal medulla of the rat kidney to study the impact of the structured organization of...
We have developed a highly detailed mathematical model of solute transport in the renal medulla of the rat kidney to study the impact of the structured organization of nephrons and vessels revealed in anatomic studies. The model represents the arrangement of tubules around a vascular bundle in the outer medulla and around a collecting duct cluster in the upper inner medulla. Model simulations yield marked gradients in intrabundle and interbundle interstitial fluid oxygen tension (PO2), NaCl concentration, and osmolality in the outer medulla, owing to the vigorous active reabsorption of NaCl by the thick ascending limbs. In the inner medulla, where the thin ascending limbs do not mediate significant active NaCl transport, interstitial fluid composition becomes much more homogeneous with respect to NaCl, urea, and osmolality. Nonetheless, a substantial PO2 gradient remains, owing to the relatively high oxygen demand of the inner medullary collecting ducts. Perhaps more importantly, the model predicts that in the absence of the three-dimensional medullary architecture, oxygen delivery to the inner medulla would drastically decrease, with the terminal inner medulla nearly completely deprived of oxygen. Thus model results suggest that the functional role of the three-dimensional medullary architecture may be to preserve oxygen delivery to the papilla. Additionally, a simulation that represents low medullary blood flow suggests that the separation of thick limbs from the vascular bundles substantially increases the risk of the segments to hypoxic injury. When nephrons and vessels are more homogeneously distributed, luminal PO2 in the thick ascending limb of superficial nephrons increases by 66% in the inner stripe. Furthermore, simulations predict that owing to the Bohr effect, the presumed greater acidity of blood in the interbundle regions, where thick ascending limbs are located, relative to that in the vascular bundles, facilitates the delivery of O2 to support the high metabolic requirements of the thick limbs and raises NaCl reabsorption.
Topics: Animals; Biological Transport; Hydrogen-Ion Concentration; Kidney Medulla; Models, Animal; Models, Theoretical; Osmolar Concentration; Oxygen; Oxygen Consumption; Rats; Sodium Chloride
PubMed: 24899054
DOI: 10.1152/ajprenal.00149.2014 -
Translational Research : the Journal of... Jun 2017The metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. Mitochondria can be overwhelmed by...
The metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. Mitochondria can be overwhelmed by substrate excess, leading to inefficient energy production and thereby tissue hypoxia. Mitochondrial dysfunction is emerging as an important determinant of renal damage, but whether it contributes to MetS-induced renal injury remains unknown. We hypothesized that early MetS induces kidney mitochondrial abnormalities and dysfunction, which would be notable in the vulnerable renal medulla. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (0.1 mg/kg SC q.d), and Lean controls (n = 7 each). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were measured in-vivo, whereas cortical and medullary mitochondrial structure and function and renal injurious pathways were studied ex-vivo. Blood pressure was slightly elevated in MetS pigs, and their renal blood flow and glomerular filtration rate were elevated. Blood oxygen level-dependent magnetic resonance imaging demonstrated that this was associated with medullary hypoxia, whereas cortical oxygenation remained intact. MetS decreased renal content of the inner mitochondrial membrane cardiolipin, particularly the tetra-linoleoyl (C18:2) cardiolipin species, and altered mitochondrial morphology and function, particularly in the medullary thick ascending limb. MetS also increased renal cytochrome-c-induced apoptosis, oxidative stress, and tubular injury. Chronic mitoprotection restored mitochondrial structure, ATP synthesis, and antioxidant defenses and decreased mitochondrial oxidative stress, medullary hypoxia, and renal injury. These findings implicate medullary mitochondrial damage in renal injury in experimental MetS, and position the mitochondria as a therapeutic target.
Topics: Animals; Cardiolipins; Diet; Female; Glomerular Filtration Rate; Kidney Medulla; Magnetic Resonance Imaging; Metabolic Syndrome; Mitochondria; Oligopeptides; Oxidative Stress; Renal Circulation; Sus scrofa
PubMed: 28363084
DOI: 10.1016/j.trsl.2017.03.002 -
Scientific Reports May 2016Classic methods for delivery of agents to specific organs are technically challenging and causes superfluous stress. The current study describes a method using...
Classic methods for delivery of agents to specific organs are technically challenging and causes superfluous stress. The current study describes a method using programmable, implantable peristaltic pumps to chronically deliver drugs in vivo, while allowing animals to remain undisturbed for accurate physiological measurements. In this study, two protocols were used to demonstrate accurate drug delivery to the renal medulla. First, the vasopressin receptor-2 agonist, dDAVP, was delivered to the renal medulla resulting in a significant increase in water retention, urine osmolality and aquaporin-2 expression and phosphorylation. Second, in a separate group of rats, the histone deacetylase (HDAC) inhibitor, MS275, was delivered to the renal medulla. HDAC inhibition resulted in a significant increase in histone H3-acetylation, the hallmark for histone deacetylase inhibition. However, this was confined to the medulla, as the histone H3-acetylation was similar in the cortex of vehicle and MS275 infused rats, suggesting targeted drug delivery without systemic spillover. Thus, implantable, peristaltic pumps provide a number of benefits compared to externalized chronic catheters and confer specific delivery to target organs.
Topics: Acetylation; Animals; Antidiuretic Agents; Aquaporin 2; Benzamides; Deamino Arginine Vasopressin; Drug Delivery Systems; Equipment Design; Histone Deacetylase Inhibitors; Histones; Infusion Pumps, Implantable; Kidney Medulla; Male; Organ Specificity; Osmolar Concentration; Pyridines; Rats; Rats, Sprague-Dawley
PubMed: 27185292
DOI: 10.1038/srep26251 -
American Journal of Physiology. Renal... Jan 2007Hypoxia inducible factor (HIF) prolyl-4-hydroxylase domain-containing proteins (PHDs) promote the degradation of HIF-1alpha. Because HIF-1alpha is highly expressed in...
Hypoxia inducible factor (HIF) prolyl-4-hydroxylase domain-containing proteins (PHDs) promote the degradation of HIF-1alpha. Because HIF-1alpha is highly expressed in the renal medulla and HIF-1alpha-targeted genes such as nitric oxide synthase, cyclooxygenase, and heme oxygenase are important in the regulation of renal medullary function, we hypothesized that PHD regulates HIF-1alpha levels in the renal medulla and, thereby, participates in the control of renal Na(+) excretion. Using real-time RT-PCR, Western blot, and immunohistochemical analyses, we have demonstrated that all three isoforms of PHD, PHD1, PHD2, and PHD3, are expressed in the kidneys and that PHD2 is the most abundant isoform. Regionally, all PHDs exhibited much higher levels in renal medulla than cortex. A furosemide-induced increase in renal medullary tissue Po(2) significantly decreased PHD levels in renal medulla, whereas hypoxia significantly increased mRNA levels of PHDs in cultured renal medullary interstitial cells, indicating that O(2) regulates PHDs. Functionally, the PHD inhibitor l-mimosine (l-Mim, 50 mg x kg(-1) x day(-1) i.p. for 2 wk) substantially upregulated HIF-1alpha expression in the kidneys, especially in the renal medulla, and remarkably enhanced (by >80%) the natriuretic response to renal perfusion pressure in Sprague-Dawley rats. Inhibition of HIF transcriptional activity by renal medullary transfection of HIF-1alpha decoy oligodeoxynucleotides attenuated l-Mim-induced enhancement of pressure natriuresis, which confirmed that HIF-1alpha mediated the effect of l-Mim. These results indicate that highly expressed PHDs in the renal medulla make an important contribution to the control of renal Na(+) excretion through regulation of HIF-1alpha and its targeted genes.
Topics: Animals; Blotting, Western; Cell Separation; Cells, Cultured; DNA-Binding Proteins; Enzyme Inhibitors; Furosemide; Heme Oxygenase-1; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Immediate-Early Proteins; Immunohistochemistry; Kidney; Kidney Medulla; Male; Mimosine; Natriuresis; Osmotic Pressure; RNA, Messenger; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Transfection
PubMed: 16885149
DOI: 10.1152/ajprenal.00457.2005