title: Hematopoietic microRNA-126 protects against renal ischemia/reperfusion injury by promoting vascular integrity.
abstract: Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. MicroRNA-126 (miR-126) facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow-derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin(-)/Sca-1(+)/cKit(+) hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin(-)/Sca-1(+)/cKit(+) cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin(-)/Sca-1(+)/cKit(+) cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell-derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Roel
authors.initials: R
authors.lastname: Bijkerk
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Coen
authors.initials: C
authors.lastname: van Solingen
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Hetty C
authors.initials: HC
authors.lastname: de Boer
authors.affiliation: Department of Nephrology.
authors.forename: Pieter
authors.initials: P
authors.lastname: van der Pol
authors.affiliation: Department of Nephrology.
authors.forename: Meriem
authors.initials: M
authors.lastname: Khairoun
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Ruben G
authors.initials: RG
authors.lastname: de Bruin
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Annemarie M
authors.initials: AM
authors.lastname: van Oeveren-Rietdijk
authors.affiliation: Department of Nephrology.
authors.forename: Ellen
authors.initials: E
authors.lastname: Lievers
authors.affiliation: Department of Nephrology.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schlagwein
authors.affiliation: Department of Nephrology.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: van Gijlswijk
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Marko K
authors.initials: MK
authors.lastname: Roeten
authors.affiliation: Department of Cardiology.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Neshati
authors.affiliation: Department of Cardiology.
authors.forename: Antoine A F
authors.initials: AA
authors.lastname: de Vries
authors.affiliation: Department of Immunohematology and Blood Transfusion, and.
authors.forename: Mark
authors.initials: M
authors.lastname: Rodijk
authors.affiliation: Department of Immunohematology and Blood Transfusion, and.
authors.forename: Karin
authors.initials: K
authors.lastname: Pike-Overzet
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yascha W
authors.initials: YW
authors.lastname: van den Berg
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Eric P
authors.initials: EP
authors.lastname: van der Veer
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henri H
authors.initials: HH
authors.lastname: Versteeg
authors.affiliation: Department of Nephrology.
authors.forename: Marlies E J
authors.initials: ME
authors.lastname: Reinders
authors.affiliation: Department of Immunohematology and Blood Transfusion, and.
authors.forename: Frank J T
authors.initials: FJ
authors.lastname: Staal
authors.affiliation: Department of Nephrology.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine, a.j.vanzonneveld@lumc.nl.
authors.forename: Anton Jan
authors.initials: AJ
authors.lastname: van Zonneveld
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D054377:Chemokine CXCL12; C545201:MIRN126 microRNA, mouse; D035683:MicroRNAs; D019718:Receptors, CXCR4