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. 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 2 /Sca-1 + /cKit + hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin 2 /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 2 /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.

Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases

“…[1][2][3][4][5][6][7] Several recent studies suggested that restoring the renal microvasculature may provide novel therapeutic options for patients with CKD. [8][9][10][11][12] Thus far, however, quantitative imaging tools allowing for the noninvasive monitoring of morphologic and functional alterations of the renal microvasculature during disease progression have been lacking, and studies investigating vessel rarefaction in CKD have been largely restricted to invasive microscopic end-point analyses. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] We here employed in vivo and ex vivo mCT-based imaging techniques, alongside conventional immunohistochemical methodologies, to demonstrate that (1) contrast-enhanced in vivo mCT imaging is highly suitable for accurate and noninvasive monitoring of vessel functionality during progressive kidney diseases, via quantifying the renal rBV; (2) the renal rBV continuously decreases during early-to-late-stage renal disease progression; (3) vessel functionality is reduced immediately after renal injury prior to the onset of interstitial fibrosis, supporting the assumption that endothelial injury might be a major initiating cause of fibrosis development; and (4) in addition to peritubular capillaries, arterial vessels of virtually all calibers undergo substantial alterations during progressive renal disease with regard to vessel branching, size, and tortuosity.…”

Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases

“…Bijkerk et al (14) showed that overexpression of miR-126 in the hematopoietic compartment can protect the kidney via preservation of microvascular integrity during ischemic renal injury and supports recovery by promoting vasculogenic progenitor cell mobilization. In another study (2), miR-127 was identified as a renoprotective miRNA during ischemic renal injury.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Apart from proangiogenic growth factors (150), several proteins have been suggested to play a role in endothelial cell remodeling leading to fibrosis including ephrin-B (208), Crim-1 (209), Id proteins (210), miR-126 (211), and the glycocalyx of glomerular endothelial cells (212). In renal transplantation, peritubular endothelial damage, in particular endothelial C4d staining, reflects rejection (213).…”