MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation

Abstract

Endothelial cells in different microvascular segments of the kidney have diverse functions and exhibit differential responsiveness to disease stimuli. The responsible molecular mechanisms are largely unknown. We previously showed that during hemorrhagic shock, VCAM-1 protein was expressed primarily in extraglomerular compartments of the kidney, while E-selectin protein was highly induced in glomeruli only (van Meurs M, Wulfert FM, Knol AJ, de Haes A, Houwertjes M, Aarts LPHJ, Molema G. Shock 29: 291–299, 2008). Here, we investigated the molecular control of expression of these endothelial cell adhesion molecules in mouse models of renal inflammation. Microvascular segment-specific responses to the induction of anti-glomerular basement membrane (anti-GBM), glomerulonephritis and systemic TNF-α treatment showed that E-selectin expression was transcriptionally regulated, with high E-selectin mRNA and protein levels preferentially expressed in the glomerular compartment. In contrast, VCAM-1 mRNA expression was increased in both arterioles and glomeruli, while VCAM-1 protein expression was limited in the glomeruli. These high VCAM-1 mRNA/low VCAM-1 protein levels were accompanied by high local microRNA (miR)-126 and Egfl7 levels, as well as higher Ets1 levels compared with arteriolar expression levels. Using miR-reporter constructs, the functional activity of miR-126 in glomerular endothelial cells could be demonstrated. Moreover, in vivo knockdown of miR-126 function unleashed VCAM-1 protein expression in the glomeruli upon inflammatory challenge. These data imply that miR-126 has a major role in the segmental, heterogenic response of renal microvascular endothelial cells to systemic inflammatory stimuli.

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

“…[29][30][31]52 For instance, it was recently shown in preeclampsia that miR-126 modulates the proangiogenic properties of EPC through targeting PI3KR2, 53 which also appears to be affected in our study Figure 2). Augmenting AKT signaling in vascular progenitor cells could be particularly relevant in kidney disease because most patients are characterized by a state of EPC dysfunction.…”

“…29 MicroRNA-126 (miR-126) is a key regulator of PI3K/AKT signaling by direct targeting of the negative regulator PI3K regulatory subunit 2 (PI3KR2/p85-b) and targets genes that play key roles in angiogenesis and inflammation. [29][30][31] In addition, miR-126 was shown to coregulate the expansion and mobilization of hematopoietic stem cells and progenitor cells. 32,33 We hypothesized that miR-126 overexpression in the hematopoietic compartment of mice can enhance the vasoprotective potential of these progenitors and that this will translate to decreased renal injury.…”

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

“…93 Modulates vascular expression of adhesion molecules. 94 Highly expressed in platelets and platelet microparticles. …”

Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker

“…miR-126 also protects against atherosclerosis by inhibiting VCAM-1 during inflammation (42,43) and contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation (44). Diabetes-induced endothelial dysfunction has been proposed as a major mechanism implicated in the pathogenesis and development of DN, occurring through activation of signal transducers of metabolic, hemodynamic and inflammatory factors (3,4), which modifies the function and morphology of neighboring cells, triggering a cascade of inflammatory, proliferative and profibrotic responses in progressive DN (4).…”