Skip to main content

Advertisement

SpringerLink
Log in

The multifaceted role of the renal microvasculature during acute kidney injury

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Pediatric acute kidney injury (AKI) represents a complex disease process for clinicians as it is multifactorial in cause and only limited treatment or preventatives are available. The renal microvasculature has recently been implicated in AKI as a strong therapeutic candidate involved in both injury and recovery. Significant progress has been made in the ability to study the renal microvasculature following ischemic AKI and its role in repair. Advances have also been made in elucidating cell–cell interactions and the molecular mechanisms involved in these interactions. The ability of the kidney to repair post AKI is closely linked to alterations in hypoxia, and these studies are elucidated in this review. Injury to the microvasculature following AKI plays an integral role in mediating the inflammatory response, thereby complicating potential therapeutics. However, recent work with experimental animal models suggests that the endothelium and its cellular and molecular interactions are attractive targets to prevent injury or hasten repair following AKI. Here, we review the cellular and molecular mechanisms of the renal endothelium in AKI, as well as repair and recovery, and potential therapeutics to prevent or ameliorate injury and hasten repair.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ricci Z, Cruz DN, Ronco C (2011) Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nat Rev Nephrol 7:201–208

    Article  CAS  PubMed  Google Scholar 

  2. Korkeila M, Ruokonen E, Takala J (2000) Costs of care, long-term prognosis and quality of life in patients requiring renal replacement therapy during intensive care. Intensive Care Med 26:1824–1831

    Article  CAS  PubMed  Google Scholar 

  3. Bagshaw SM (2006) The long-term outcome after acute renal failure. Curr Opin Crit Care 12:561–566

    Article  PubMed  Google Scholar 

  4. Chan JC, Williams DM, Roth KS (2002) Kidney failure in infants and children. Pediatr Rev 23:47–60

    Article  PubMed  Google Scholar 

  5. Patzer L (2008) Nephrotoxicity as a cause of acute kidney injury in children. Pediatr Nephrol 23:2159–2173

    Article  PubMed  Google Scholar 

  6. Faught LN, Greff MJ, Rieder MJ, Koren G (2015) Drug-induced acute kidney injury in children. Br J Clin Pharmacol 80(4):901–909

  7. Andreoli SP (2009) Acute kidney injury in children. Pediatr Nephrol 24:253–263

    Article  PubMed  Google Scholar 

  8. Bentley ML, Corwin HL, Dasta J (2010) Drug-induced acute kidney injury in the critically ill adult: recognition and prevention strategies. Crit Care Med 38:S169–S174

    Article  CAS  PubMed  Google Scholar 

  9. Ashraf M, Shahzad N, Irshad M, Hussain SQ, Ahmed P (2014) Pediatric acute kidney injury: a syndrome under paradigm shift. Indian J Crit Care Med 18:518–526

    Article  PubMed  PubMed Central  Google Scholar 

  10. Aggarwal A, Kumar P, Chowdhary G, Majumdar S, Narang A (2005) Evaluation of renal functions in asphyxiated newborns. J Trop Pediatr 51:295–299

    Article  PubMed  Google Scholar 

  11. Hum S, Rymer C, Schaefer C, Bushnell D, Sims-Lucas S (2014) Ablation of the renal stroma defines its critical role in nephron progenitor and vasculature patterning. PLoS One 9, e88400

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Sariola H (2002) Nephron induction. Nephrol Dial Transplant 17[Suppl 9]:88–90

    Article  CAS  PubMed  Google Scholar 

  13. Saxen L, Sariola H (1987) Early organogenesis of the kidney. Pediatr Nephrol 1:385–392

    Article  CAS  PubMed  Google Scholar 

  14. Kanwar YS, Carone FA, Kumar A, Wada J, Ota K, Wallner EI (1997) Role of extracellular matrix, growth factors and proto-oncogenes in metanephric development. Kidney Int 52:589–606

    Article  CAS  PubMed  Google Scholar 

  15. Alcorn D, Maric C, McCausland J (1999) Development of the renal interstitium. Pediatr Nephrol 13:347–354

    Article  CAS  PubMed  Google Scholar 

  16. Sims-Lucas S, Schaefer C, Bushnell D, Ho J, Logar A, Prochownik E, Gittes G, Bates CM (2013) Endothelial progenitors exist within the kidney and lung mesenchyme. PLoS One 8:e65993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sequeira Lopez ML, Gomez RA (2011) Development of the renal arterioles. J Am Soc Nephrol 22:2156–2165

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Sequeira-Lopez ML, Lin EE, Li M, Hu Y, Sigmund CD, Gomez RA (2015) The earliest metanephric arteriolar progenitors and their role in kidney vascular development. Am J Physiol Regul Integr Comp Physiol 308:R138–R149

    Article  CAS  PubMed  Google Scholar 

  19. Levinson RS, Batourina E, Choi C, Vorontchikhina M, Kitajewski J, Mendelsohn CL (2005) Foxd1-dependent signals control cellularity in the renal capsule, a structure required for normal renal development. Development 132:529–539

    Article  CAS  PubMed  Google Scholar 

  20. Hatini V, Huh SO, Herzlinger D, Soares VC, Lai E (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev 10:1467–1478

    Article  CAS  PubMed  Google Scholar 

  21. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176:85–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Smadja DM, d’Audigier C, Bieche I, Evrard S, Mauge L, Dias JV, Labreuche J, Laurendeau I, Marsac B, Dizier B, Wagner-Ballon O, Boisson-Vidal C, Morandi V, Duong-Van-Huyen JP, Bruneval P, Dignat-George F, Emmerich J, Gaussem P (2011) Thrombospondin-1 is a plasmatic marker of peripheral arterial disease that modulates endothelial progenitor cell angiogenic properties. Arterioscler Thromb Vasc Biol 31:551–559

    Article  CAS  PubMed  Google Scholar 

  23. Roberts DD, Miller TW, Rogers NM, Yao M, Isenberg JS (2012) The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress via CD47. Matrix Biol 31:162–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kramann R, Tanaka M, Humphreys BD (2014) Fluorescence microangiography for quantitative assessment of peritubular capillary changes after AKI in mice. J Am Soc Nephrol 25:1924–1931

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lubbers DW, Baumgartl H (1997) Heterogeneities and profiles of oxygen pressure in brain and kidney as examples of the pO2 distribution in the living tissue. Kidney Int 51:372–380

    Article  CAS  PubMed  Google Scholar 

  26. Eckardt KU, Bernhardt WM, Weidemann A, Warnecke C, Rosenberger C, Wiesener MS, Willam C (2005) Role of hypoxia in the pathogenesis of renal disease. Kidney Int Suppl (99):S46–51

  27. Malek M, Nematbakhsh M (2015) Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev 4:20–27

    PubMed  PubMed Central  Google Scholar 

  28. Kimura N, Kimura H, Takahashi N, Hamada T, Maegawa H, Mori M, Imamura Y, Kusaka Y, Yoshida H, Iwano M (2015) Renal resistive index correlates with peritubular capillary loss and arteriosclerosis in biopsy tissues from patients with chronic kidney disease. Clin Exp Nephrol. doi:10.1007/s10157-015-1116-0

  29. Isenberg JS, Hyodo F, Matsumoto K, Romeo MJ, Abu-Asab M, Tsokos M, Kuppusamy P, Wink DA, Krishna MC, Roberts DD (2007) Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. Blood 109:1945–1952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Basile DP (2007) The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int 72:151–156

    Article  CAS  PubMed  Google Scholar 

  31. Basile DP (2004) Rarefaction of peritubular capillaries following ischemic acute renal failure: a potential factor predisposing to progressive nephropathy. Curr Opin Nephrol Hypertens 13:1–7

    Article  PubMed  Google Scholar 

  32. Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL (2006) 3–5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 69:184–189

    Article  CAS  PubMed  Google Scholar 

  33. Brodsky SV, Yamamoto T, Tada T, Kim B, Chen J, Kajiya F, Goligorsky MS (2002) Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol 282:F1140–F1149

    Article  CAS  PubMed  Google Scholar 

  34. Basile DP, Yoder MC (2014) Renal endothelial dysfunction in acute kidney ischemia reperfusion injury. Cardiovasc Hematol Disord Drug Targets 14:3–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Arriero M, Brodsky SV, Gealekman O, Lucas PA, Goligorsky MS (2004) Adult skeletal muscle stem cells differentiate into endothelial lineage and ameliorate renal dysfunction after acute ischemia. Am J Physiol Renal Physiol 287:F621–F627

    Article  CAS  PubMed  Google Scholar 

  36. Choong FX, Sandoval RM, Molitoris BA, Richter-Dahlfors A (2012) Multiphoton microscopy applied for real-time intravital imaging of bacterial infections in vivo. Methods Enzymol 506:35–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Molitoris BA (2014) Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J Clin Invest 124:2355–2363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Grenz A, Bauerle JD, Dalton JH, Ridyard D, Badulak A, Tak E, McNamee EN, Clambey E, Moldovan R, Reyes G, Klawitter J, Ambler K, Magee K, Christians U, Brodsky KS, Ravid K, Choi DS, Wen J, Lukashev D, Blackburn MR, Osswald H, Coe IR, Nurnberg B, Haase VH, Xia Y, Sitkovsky M, Eltzschig HK (2012) Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. J Clin Invest 122:693–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mattson DL, Lu S, Cowley AW Jr (1997) Role of nitric oxide in the control of the renal medullary circulation. Clin Exp Pharmacol Physiol 24:587–590

    Article  CAS  PubMed  Google Scholar 

  40. Kang DH, Joly AH, Oh SW, Hugo C, Kerjaschki D, Gordon KL, Mazzali M, Jefferson JA, Hughes J, Madsen KM, Schreiner GF, Johnson RJ (2001) Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. J Am Soc Nephrol 12:1434–1447

    CAS  PubMed  Google Scholar 

  41. O’Riordan E, Mendelev N, Patschan S, Patschan D, Eskander J, Cohen-Gould L, Chander P, Goligorsky MS (2007) Chronic NOS inhibition actuates endothelial-mesenchymal transformation. Am J Physiol Heart Circ Physiol 292:H285–H294

    Article  PubMed  CAS  Google Scholar 

  42. Lin SL, Chang FC, Schrimpf C, Chen YT, Wu CF, Wu VC, Chiang WC, Kuhnert F, Kuo CJ, Chen YM, Wu KD, Tsai TJ, Duffield JS (2011) Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol 178:911–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sharfuddin AA, Molitoris BA (2011) Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 7:189–200

    Article  CAS  PubMed  Google Scholar 

  44. Weinberg JM, Venkatachalam MA (2012) Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine. J Clin Invest 122:493–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang HC, Shi GY, Jiang SJ, Shi CS, Wu CM, Yang HY, Wu HL (2003) Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. J Biol Chem 278:46750–46759

    Article  CAS  PubMed  Google Scholar 

  46. Esmon CT, Owen WG (2004) The discovery of thrombomodulin. J Thromb Haemost 2:209–213

    Article  CAS  PubMed  Google Scholar 

  47. Ling H, Edelstein C, Gengaro P, Meng X, Lucia S, Knotek M, Wangsiripaisan A, Shi Y, Schrier R (1999) Attenuation of renal ischemia-reperfusion injury in inducible nitric oxide synthase knockout mice. Am J Physiol 277:F383–F390

    CAS  PubMed  Google Scholar 

  48. Thakar CV, Zahedi K, Revelo MP, Wang Z, Burnham CE, Barone S, Bevans S, Lentsch AB, Rabb H, Soleimani M (2005) Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia. J Clin Invest 115:3451–3459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rogers NM, Thomson AW, Isenberg JS (2012) Activation of parenchymal CD47 promotes renal ischemia–reperfusion injury. J Am Soc Nephrol 23:1538–1550

  50. Isenberg JS, Ridnour LA, Perruccio EM, Espey MG, Wink DA, Roberts DD (2005) Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc Natl Acad Sci USA 102:13141–13146

  51. Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD (2006) CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1. J Biol Chem 281:26069–26080

    Article  CAS  PubMed  Google Scholar 

  52. Martinez-Mier G, Toledo-Pereyra LH, Bussell S, Gauvin J, Vercruysse G, Arab A, Harkema JR, Jordan JA, Ward PA (2000) Nitric oxide diminishes apoptosis and p53 gene expression after renal ischemia and reperfusion injury. Transplantation 70:1431–1437

    Article  CAS  PubMed  Google Scholar 

  53. Rodriguez-Pena A, Garcia-Criado FJ, Eleno N, Arevalo M, Lopez-Novoa JM (2004) Intrarenal administration of molsidomine, a molecule releasing nitric oxide, reduces renal ischemia–reperfusion injury in rats. Am J Transplant 4:1605–1613

  54. Liu X, Huang Y, Pokreisz P, Vermeersch P, Marsboom G, Swinnen M, Verbeken E, Santos J, Pellens M, Gillijns H, Van de Werf F, Bloch KD, Janssens S (2007) Nitric oxide inhalation improves microvascular flow and decreases infarction size after myocardial ischemia and reperfusion. J Am Coll Cardiol 50:808–817

    Article  PubMed  CAS  Google Scholar 

  55. Lang JD Jr, Teng X, Chumley P, Crawford JH, Isbell TS, Chacko BK, Liu Y, Jhala N, Crowe DR, Smith AB, Cross RC, Frenette L, Kelley EE, Wilhite DW, Hall CR, Page GP, Fallon MB, Bynon JS, Eckhoff DE, Patel RP (2007) Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J Clin Invest 117:2583–2591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sutton TA, Fisher CJ, Molitoris BA (2002) Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 62:1539–1549

    Article  CAS  PubMed  Google Scholar 

  57. Perez Fontan M, Rodriguez-Carmona A, Bouza P, Valdes F (1998) The prognostic significance of acute renal failure after renal transplantation in patients treated with cyclosporin. QJM 91:27–40

    Article  CAS  PubMed  Google Scholar 

  58. Verma SK, Molitoris BA (2015) Renal endothelial injury and microvascular dysfunction in acute kidney injury. Semin Nephrol 35:96–107

    Article  CAS  PubMed  Google Scholar 

  59. Basile DP, Donohoe D, Roethe K, Osborn JL (2001) Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 281:F887–F899

    Article  CAS  PubMed  Google Scholar 

  60. Yamamoto T, Tada T, Brodsky SV, Tanaka H, Noiri E, Kajiya F, Goligorsky MS (2002) Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am J Physiol Renal Physiol 282:F1150–F1155

    Article  CAS  PubMed  Google Scholar 

  61. Dimke H, Sparks MA, Thomson BR, Frische S, Coffman TM, Quaggin SE (2015) Tubulovascular cross-talk by vascular endothelial growth factor a maintains peritubular microvasculature in kidney. J Am Soc Nephrol 26:1027–1038

    Article  CAS  PubMed  Google Scholar 

  62. Mansson LE, Melican K, Boekel J, Sandoval RM, Hautefort I, Tanner GA, Molitoris BA, Richter-Dahlfors A (2007) Real-time studies of the progression of bacterial infections and immediate tissue responses in live animals. Cell Microbiol 9:413–424

    Article  PubMed  CAS  Google Scholar 

  63. Melican K, Boekel J, Mansson LE, Sandoval RM, Tanner GA, Kallskog O, Palm F, Molitoris BA, Richter-Dahlfors A (2008) Bacterial infection-mediated mucosal signalling induces local renal ischaemia as a defence against sepsis. Cell Microbiol 10:1987–1998

    Article  CAS  PubMed  Google Scholar 

  64. Vallon V, Osswald H (2009) Adenosine receptors and the kidney. Handb Exp Pharmacol 2009:443–470

  65. Yap SC, Lee HT (2012) Adenosine and protection from acute kidney injury. Curr Opin Nephrol Hypertens 21:24–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Vallon V, Muhlbauer B, Osswald H (2006) Adenosine and kidney function. Physiol Rev 86:901–940

    Article  CAS  PubMed  Google Scholar 

  67. Chawla LS, Kimmel PL (2012) Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int 82:516–524

    Article  PubMed  Google Scholar 

  68. Tanaka T, Nangaku M (2013) Angiogenesis and hypoxia in the kidney. Nat Rev Nephrol 9:211–222

    Article  CAS  PubMed  Google Scholar 

  69. Ergin B, Kapucu A, Demirci-Tansel C, Ince C (2015) The renal microcirculation in sepsis. Nephrol Dial Transplant 30:169–177

    Article  PubMed  Google Scholar 

  70. Kapitsinou PP, Sano H, Michael M, Kobayashi H, Davidoff O, Bian A, Yao B, Zhang MZ, Harris RC, Duffy KJ, Erickson-Miller CL, Sutton TA, Haase VH (2014) Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J Clin Invest 124:2396–2409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Advani A, Connelly KA, Yuen DA, Zhang Y, Advani SL, Trogadis J, Kabir MG, Shachar E, Kuliszewski MA, Leong-Poi H, Stewart DJ, Gilbert RE (2011) Fluorescent microangiography is a novel and widely applicable technique for delineating the renal microvasculature. PLoS One 6, e24695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sutton TA, Mang HE, Campos SB, Sandoval RM, Yoder MC, Molitoris BA (2003) Injury of the renal microvascular endothelium alters barrier function after ischemia. Am J Physiol Renal Physiol 285:F191–F198

    Article  CAS  PubMed  Google Scholar 

  73. Kwon O, Phillips CL, Molitoris BA (2002) Ischemia induces alterations in actin filaments in renal vascular smooth muscle cells. Am J Physiol Renal Physiol 282:F1012–F1019

    Article  CAS  PubMed  Google Scholar 

  74. Becherucci F, Mazzinghi B, Ronconi E, Peired A, Lazzeri E, Sagrinati C, Romagnani P, Lasagni L (2009) The role of endothelial progenitor cells in acute kidney injury. Blood Purif 27:261–270

    Article  PubMed  Google Scholar 

  75. Basile DP, Anderson MD, Sutton TA (2012) Pathophysiology of acute kidney injury. Compr Physiol 2:1303–1353

    PubMed  PubMed Central  Google Scholar 

  76. Jang HR, Rabb H (2009) The innate immune response in ischemic acute kidney injury. Clin Immunol 130:41–50

    Article  CAS  PubMed  Google Scholar 

  77. Bonventre JV, Zuk A (2004) Ischemic acute renal failure: an inflammatory disease? Kidney Int 66:480–485

    Article  CAS  PubMed  Google Scholar 

  78. Goncalves GM, Zamboni DS, Camara NO (2010) The role of innate immunity in septic acute kidney injuries. Shock 34[Suppl 1]:22–26

    Article  CAS  PubMed  Google Scholar 

  79. Jang HR, Rabb H (2015) Immune cells in experimental acute kidney injury. Nat Rev Nephrol 11:88–101

    Article  CAS  PubMed  Google Scholar 

  80. Jang HR, Ko GJ, Wasowska BA, Rabb H (2009) The interaction between ischemia-reperfusion and immune responses in the kidney. J Mol Med (Berl) 87:859–864

    Article  CAS  Google Scholar 

  81. Ysebaert DK, De Greef KE, Vercauteren SR, Ghielli M, Verpooten GA, Eyskens EJ, De Broe ME (2000) Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant 15:1562–1574

    Article  CAS  PubMed  Google Scholar 

  82. Celie JW, Rutjes NW, Keuning ED, Soininen R, Heljasvaara R, Pihlajaniemi T, Drager AM, Zweegman S, Kessler FL, Beelen RH, Florquin S, Aten J, van den Born J (2007) Subendothelial heparan sulfate proteoglycans become major L-selectin and monocyte chemoattractant protein-1 ligands upon renal ischemia/reperfusion. Am J Pathol 170:1865–1878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Anders HJ, Vielhauer V, Schlondorff D (2003) Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Kidney Int 63:401–415

    Article  CAS  PubMed  Google Scholar 

  84. Swaminathan S, Griffin MD (2008) First responders: understanding monocyte-lineage traffic in the acutely injured kidney. Kidney Int 74:1509–1511

    Article  CAS  PubMed  Google Scholar 

  85. Duffield JS (2010) Macrophages and immunologic inflammation of the kidney. Semin Nephrol 30:234–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chiba T, Skrypnyk NI, Skvarca LB, Penchev R, Zhang KX, Rochon ER, Fall JL, Paueksakon P, Yang H, Alford CE, Roman BL, Zhang MZ, Harris R, Hukriede NA, de Caestecker MP (2015) Retinoic acid signaling coordinates macrophage-dependent injury and repair after AKI. J Am Soc Nephrol [Epub ahead of print]

  87. Huen SC, Huynh L, Marlier A, Lee Y, Moeckel GW, Cantley LG (2015) GM-CSF promotes macrophage alternative activation after renal ischemia/reperfusion injury. J Am Soc Nephrol 26:1334–1345

    Article  CAS  PubMed  Google Scholar 

  88. Chiao H, Kohda Y, McLeroy P, Craig L, Housini I, Star RA (1997) Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest 99:1165–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nemoto T, Burne MJ, Daniels F, O’Donnell MP, Crosson J, Berens K, Issekutz A, Kasiske BL, Keane WF, Rabb H (2001) Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure. Kidney Int 60:2205–2214

    Article  CAS  PubMed  Google Scholar 

  90. Solez K, Morel-Maroger L, Sraer JD (1979) The morphology of “acute tubular necrosis” in man: analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine (Baltimore) 58:362–376

    Article  CAS  Google Scholar 

  91. Friedewald JJ, Rabb H (2004) Inflammatory cells in ischemic acute renal failure. Kidney Int 66:486–491

    Article  PubMed  Google Scholar 

  92. Rosenberger C, Griethe W, Gruber G, Wiesener M, Frei U, Bachmann S, Eckardt KU (2003) Cellular responses to hypoxia after renal segmental infarction. Kidney Int 64:874–886

    Article  PubMed  Google Scholar 

  93. Lichtnekert J, Kawakami T, Parks WC, Duffield JS (2013) Changes in macrophage phenotype as the immune response evolves. Curr Opin Pharmacol 13:555–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  CAS  PubMed  Google Scholar 

  95. Gandolfo MT, Jang HR, Bagnasco SM, Ko GJ, Agreda P, Satpute SR, Crow MT, King LS, Rabb H (2009) Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int 76:717–729

    Article  CAS  PubMed  Google Scholar 

  96. Kinsey GR, Sharma R, Huang L, Li L, Vergis AL, Ye H, Ju ST, Okusa MD (2009) Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J Am Soc Nephrol 20:1744–1753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kim MG, Koo TY, Yan JJ, Lee E, Han KH, Jeong JC, Ro H, Kim BS, Jo SK, Oh KH, Surh CD, Ahn C, Yang J (2013) IL-2/anti-IL-2 complex attenuates renal ischemia-reperfusion injury through expansion of regulatory T cells. J Am Soc Nephrol 24:1529–1536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gupta A, Berg DT, Gerlitz B, Sharma GR, Syed S, Richardson MA, Sandusky G, Heuer JG, Galbreath EJ, Grinnell BW (2007) Role of protein C in renal dysfunction after polymicrobial sepsis. J Am Soc Nephrol 18:860–867

    Article  CAS  PubMed  Google Scholar 

  99. Bouchard J, Malhotra R, Shah S, Kao YT, Vaida F, Gupta A, Berg DT, Grinnell BW, Stofan B, Tolwani AJ, Mehta RL (2015) Levels of protein C and soluble thrombomodulin in critically ill patients with acute kidney injury: a multicenter prospective observational study. PLoS One 10:e0120770

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Mizutani A, Okajima K, Uchiba M, Noguchi T (2000) Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood 95:3781–3787

    CAS  PubMed  Google Scholar 

  101. Sharfuddin AA, Sandoval RM, Berg DT, McDougal GE, Campos SB, Phillips CL, Jones BE, Gupta A, Grinnell BW, Molitoris BA (2009) Soluble thrombomodulin protects ischemic kidneys. J Am Soc Nephrol 20:524–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ikeguchi H, Maruyama S, Morita Y, Fujita Y, Kato T, Natori Y, Akatsu H, Campbell W, Okada N, Okada H, Yuzawa Y, Matsuo S (2002) Effects of human soluble thrombomodulin on experimental glomerulonephritis. Kidney Int 61:490–501

    Article  CAS  PubMed  Google Scholar 

  103. Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H, De Vriese A, Weitz JI, Weiler H, Hellings PW, Schaeffer P, Herbert JM, Collen D, Theilmeier G (2002) The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med 196:565–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Noiri E, Nakao A, Uchida K, Tsukahara H, Ohno M, Fujita T, Brodsky S, Goligorsky MS (2001) Oxidative and nitrosative stress in acute renal ischemia. Am J Physiol Renal Physiol 281:F948–F957

    Article  CAS  PubMed  Google Scholar 

  105. Goligorsky MS, Brodsky SV, Noiri E (2004) NO bioavailability, endothelial dysfunction, and acute renal failure: new insights into pathophysiology. Semin Nephrol 24:316–323

    Article  CAS  PubMed  Google Scholar 

  106. Mattson DL, Wu F (2000) Control of arterial blood pressure and renal sodium excretion by nitric oxide synthase in the renal medulla. Acta Physiol Scand 168:149–154

    Article  CAS  PubMed  Google Scholar 

  107. Chander V, Chopra K (2005) Renal protective effect of molsidomine and L-arginine in ischemia-reperfusion induced injury in rats. J Surg Res 128:132–139

    Article  CAS  PubMed  Google Scholar 

  108. Basile DP, Fredrich K, Chelladurai B, Leonard EC, Parrish AR (2008) Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor. Am J Physiol Renal Physiol 294:F928–F936

    Article  CAS  PubMed  Google Scholar 

  109. Leonard EC, Friedrich JL, Basile DP (2008) VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am J Physiol Renal Physiol 295:F1648–F1657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A (2009) Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther 86:396–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, Pavenstadt H, Lanvers-Kaminsky C, am Zehnhoff-Dinnesen A, Schinkel AH, Koepsell H, Jurgens H, Schlatter E (2010) Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol 176:1169–1180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sprowl JA, Lancaster CS, Pabla N, Hermann E, Kosloske AM, Gibson AA, Li L, Zeeh D, Schlatter E, Janke LJ, Ciarimboli G, Sparreboom A (2014) Cisplatin-induced renal injury is independently mediated by OCT2 and p53. Clin Cancer Res 20:4026–4035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pabla N, Gibson AA, Buege M, Ong SS, Li L, Hu S, Du G, Sprowl JA, Vasilyeva A, Janke LJ, Schlatter E, Chen T, Ciarimboli G, Sparreboom A (2015) Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions. Proc Natl Acad Sci USA 112:5231–5236

  114. Molitoris BA, Melnikov VY, Okusa MD, Himmelfarb J (2008) Technology Insight: biomarker development in acute kidney injury--what can we anticipate? Nat Clin Pract Nephrol 4:154–165

    Article  CAS  PubMed  Google Scholar 

  115. Lorenzen JM, Kielstein JT, Hafer C, Gupta SK, Kumpers P, Faulhaber-Walter R, Haller H, Fliser D, Thum T (2011) Circulating miR-210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 6:1540–1546

    Article  CAS  PubMed  Google Scholar 

  116. Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, Capogrossi MC, Martelli F (2008) MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J Biol Chem 283:15878–15883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Molitoris JK, Molitoris BA (2011) Circulating micro-RNAs in acute kidney injury: early observations. Clin J Am Soc Nephrol 6:1517–1519

    Article  CAS  PubMed  Google Scholar 

  118. Cantaluppi V, Gatti S, Medica D, Figliolini F, Bruno S, Deregibus MC, Sordi A, Biancone L, Tetta C, Camussi G (2012) Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int 82:412–427

    Article  CAS  PubMed  Google Scholar 

  119. Bitzer M, Ben-Dov IZ, Thum T (2012) Microparticles and microRNAs of endothelial progenitor cells ameliorate acute kidney injury. Kidney Int 82:375–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bellomo R, Kellum JA, Ronco C (2012) Acute kidney injury. Lancet 380:756–766

    Article  PubMed  Google Scholar 

  121. Ferenbach DA, Bonventre JV (2015) Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol 11:264–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by an NIH K01 DK096996 (SSL) and an NIH T32 DK061296 (KM).

Author information

Authors and Affiliations

  1. Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

    Katherine Maringer & Sunder Sims-Lucas

  2. Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Katherine Maringer & Sunder Sims-Lucas

  3. Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Sunder Sims-Lucas

Authors
  1. Katherine Maringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sunder Sims-Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sunder Sims-Lucas.

Ethics declarations

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maringer, K., Sims-Lucas, S. The multifaceted role of the renal microvasculature during acute kidney injury. Pediatr Nephrol 31, 1231–1240 (2016). https://doi.org/10.1007/s00467-015-3231-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-015-3231-2

Keywords

Search

Navigation