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: Roel Bijkerk, Coen van Solingen, Hetty C de Boer, Pieter van der Pol, Meriem Khairoun, Ruben G de Bruin, Annemarie M van Oeveren-Rietdijk, Ellen Lievers, Nicole Schlagwein, Danielle J van Gijlswijk, Marko K Roeten, Zeinab Neshati, Antoine A F de Vries, Mark Rodijk, Karin Pike-Overzet, Yascha W van den Berg, Eric P van der Veer, Henri H Versteeg, Marlies E J Reinders, Frank J T Staal, Cees van Kooten, Ton J Rabelink, Anton Jan van Zonneveld
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 25 Issue 8 Pg. 1710-22 (Aug 2014) ISSN: 1533-3450 [Electronic] United States
• PMID: 24610930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by the American Society of Nephrology.

Chemical References

• Chemokine CXCL12
• MIRN126 microRNA, mouse
• MicroRNAs
• Receptors, CXCR4

Topics

• Acute Kidney Injury (metabolism, pathology, prevention & control)
• Animals
• Cell Movement (physiology)
• Chemokine CXCL12 (metabolism)
• Hematopoietic Stem Cells (physiology)
• Kidney (blood supply, metabolism, pathology)
• Male
• Mice, Inbred C57BL
• MicroRNAs (physiology)
• Neovascularization, Physiologic (physiology)
• Receptors, CXCR4 (metabolism)
• Reperfusion Injury (metabolism, pathology, prevention & control)