title: Impacts of nitric oxide and superoxide on renal medullary oxygen transport and urine concentration.
abstract: 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.
authors: Department of Mathematics, Duke University, Durham, North Carolina; and bfry@math.duke.edu.
authors: Brendan C
authors: BC
authors: Fry
authors: University of Paris 6, University of Paris 5, Institut National de la Santé et de la Recherche Médicale UMRS 1138, Centre National de la Recherche Scientifique ERL 8228, Centre de Recherche des Cordeliers, Paris, France.
authors: Aurélie
authors: A
authors: Edwards
authors: Department of Mathematics, Duke University, Durham, North Carolina; and.
authors: Anita T
authors: AT
authors: Layton
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001692:Biological Transport; D015687:Cell Hypoxia; D003198:Computer Simulation; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D007671:Kidney Concentrating Ability; D007679:Kidney Medulla / Q000098:blood supply* / Q000378:metabolism* / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism / Q000503:physiopathology; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D017711:Nonlinear Dynamics; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D012079:Renal Circulation; D012964:Sodium / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
chemical_list: D013481:Superoxides; D009569:Nitric Oxide; D012964:Sodium; D010100:Oxygen
keywords: hypoxia; mathematical model; oxygen; sodium transport
references: Am J Physiol Renal Physiol. 2005 Oct;289(4):F749-53
references: 15942050
references: Am J Physiol Regul Integr Comp Physiol. 2005 Nov;289(5):R1459-66
references: 15947068
references: Am J Physiol Renal Physiol. 2005 Dec;289(6):F1346-66
references: 15914776
references: Hypertension. 2008 Nov;52(5):777-86
references: 18852392
references: Circulation. 2009 Feb 3;119(4):495-502
references: 19153273
references: Am J Physiol Renal Physiol. 2009 Aug;297(2):F517-36
references: 19403646
references: Hypertension. 2009 Dec;54(6):1291-7
references: 19805644
references: Hypertension. 2010 Feb;55(2):298-304
references: 20048199
references: Am J Physiol Regul Integr Comp Physiol. 2006 Jan;290(1):R79-83
references: 16099821
references: Am J Physiol Renal Physiol. 2006 Jun;290(6):F1355-66
references: 16380456
references: Clin Exp Pharmacol Physiol. 2006 Oct;33(10):1002-5
references: 17002680
references: Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R1-17
references: 16990493
references: Am J Physiol Renal Physiol. 2007 Apr;292(4):F1105-23
references: 17229679
references: Am J Physiol Renal Physiol. 2007 Sep;293(3):F696-704
references: 17609288
references: Hypertension. 2008 Feb;51(2):345-51
references: 18158356
references: Am J Physiol Renal Physiol. 2010 Sep;299(3):F616-33
references: 20534869
references: Am J Physiol Renal Physiol. 2011 Feb;300(2):F356-71
references: 21068086
references: Am J Physiol Renal Physiol. 2011 Feb;300(2):F372-84
references: 21068088
references: Am J Physiol Renal Physiol. 2011 Nov;301(5):F979-96
references: 21849492
references: Am J Physiol Regul Integr Comp Physiol. 2011 Nov;301(5):R1229-41
references: 21832206
references: Am J Physiol Renal Physiol. 2012 Mar 1;302(5):F591-605
references: 22088433
references: Am J Physiol Renal Physiol. 2012 Mar 15;302(6):F679-87
references: 22169010
references: Am J Physiol Regul Integr Comp Physiol. 2012 Jun 15;302(12):R1443-9
references: 22552796
references: Am J Physiol Renal Physiol. 2013 Mar 15;304(6):F653-64
references: 23097466
references: Am J Physiol Renal Physiol. 2013 Jun 1;304(11):F1390-7
references: 23515718
references: Am J Physiol Regul Integr Comp Physiol. 2014 Jan 1;306(1):R45-50
references: 24226029
references: Am J Physiol Renal Physiol. 2014 May 1;306(9):F952-69
references: 24553433
references: Am J Physiol Renal Physiol. 2014 Jun 1;306(11):F1357-71
references: 24623150
references: Am J Physiol Renal Physiol. 2014 Aug 1;307(3):F263-72
references: 24899054
references: Hypertension. 2000 Mar;35(3):740-5
references: 10720588
references: Exp Physiol. 2000 Mar;85 Spec No:223S-231S
references: 10795926
references: Am J Physiol Regul Integr Comp Physiol. 2000 Sep;279(3):R769-77
references: 10956233
references: Kidney Int. 2001 Jan;59(1):230-7
references: 11135075
references: Hypertension. 2001 Feb;37(2 Pt 2):547-53
references: 11230333
references: J Hypertens. 2001 Mar;19(3 Pt 2):649-57
references: 11327642
references: Am J Hypertens. 2001 Jun;14(6 Pt 2):68S-73S
references: 11411768
references: Am J Physiol Renal Physiol. 2001 Nov;281(5):F819-25
references: 11592939
references: Hypertension. 2002 Feb;39(2 Pt 2):667-72
references: 11882628
references: Am J Physiol Renal Physiol. 2002 May;282(5):F777-84
references: 11934686
references: Circulation. 2002 Apr 9;105(14):1656-62
references: 11940543
references: Am J Physiol Renal Physiol. 2002 Jun;282(6):F1111-9
references: 11997328
references: Am J Physiol Renal Physiol. 2002 Nov;283(5):F957-62
references: 12372771
references: Am J Physiol Regul Integr Comp Physiol. 2003 May;284(5):R1153-75
references: 12676741
references: Am J Physiol Regul Integr Comp Physiol. 2003 Jun;284(6):R1355-69
references: 12736168
references: Free Radic Biol Med. 2003 Jun 1;34(11):1488-503
references: 12757859
references: J Am Soc Nephrol. 2003 Aug;14(8):2178-87
references: 12874474
references: Acta Physiol Scand. 2003 Nov;179(3):225-32
references: 14616238
references: Am J Physiol Renal Physiol. 2004 Jan;286(1):F38-45
references: 14519595
references: Am J Physiol Renal Physiol. 2004 Oct;287(4):F767-74
references: 15187004
references: Clin Pharmacokinet. 1979 May-Jun;4(3):200-22
references: 383355
references: Pflugers Arch. 1983 Mar;396(4):308-14
references: 6844135
references: Am J Physiol. 1985 Apr;248(4 Pt 2):F522-6
references: 3985159
references: J Clin Invest. 1986 Jan;77(1):113-20
references: 2418058
references: Am J Physiol. 1987 Mar;252(3 Pt 2):F480-6
references: 3826388
references: Kidney Int. 1987 Feb;31(2):538-48
references: 3550222
references: Am J Physiol. 1987 Aug;253(2 Pt 2):F251-62
references: 3303974
references: Am J Physiol. 1988 Nov;255(5 Pt 2):F977-83
references: 2847554
references: Am J Physiol. 1990 Jun;258(6 Pt 2):F1608-15
references: 2163215
references: Am J Physiol. 1991 Nov;261(5 Pt 2):F904-19
references: 1951721
references: Physiol Rev. 1994 Jul;74(3):637-81
references: 8036249
references: Am J Physiol. 1997 Jan;272(1 Pt 2):F147-51
references: 9039061
references: Am J Physiol. 1997 Feb;272(2 Pt 2):F242-8
references: 9124402
references: Am J Physiol. 1997 Jun;272(6 Pt 1):L1161-6
references: 9227518
references: Hypertension. 1998 Jan;31(1 Pt 2):271-6
references: 9453315
references: Am J Physiol. 1998 May;274(5 Pt 2):F841-55
references: 9612321
references: Kidney Int. 1998 Dec;54(6):1817-31
references: 9853246
references: Am J Physiol. 1999 Jan;276(1 Pt 2):F159-63
references: 9887091
references: Hypertension. 1999 Jan;33(1 Pt 2):446-50
references: 9931145
references: Am J Physiol. 1999 Jun;276(6 Pt 2):F874-81
references: 10362776
references: Am J Physiol Renal Physiol. 2004 Dec;287(6):F1189-203
references: 15280161
references: Am J Physiol Regul Integr Comp Physiol. 2004 Dec;287(6):R1478-85
references: 15319219
references: Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H22-8
references: 15598867