miR-127 Protects Proximal Tubule Cells against Ischemia/Reperfusion: Identification of Kinesin Family Member 3B as miR-127 Target

Abstract

Ischemia/reperfusion (I/R) is at the basis of renal transplantation and acute kidney injury. Molecular mechanisms underlying proximal tubule response to I/R will allow the identification of new therapeutic targets for both clinical settings. microRNAs have emerged as crucial and tight regulators of the cellular response to insults including hypoxia. Here, we have identified several miRNAs involved in the response of the proximal tubule cell to I/R. Microarrays and RT-PCR analysis of proximal tubule cells submitted to I/R mimicking conditions in vitro demonstrated that miR-127 is induced during ischemia and also during reperfusion. miR-127 is also modulated in a rat model of renal I/R. Interference approaches demonstrated that ischemic induction of miR-127 is mediated by Hypoxia Inducible Factor-1alpha (HIF-1α) stabilization. Moreover, miR-127 is involved in cell-matrix and cell-cell adhesion maintenance, since overexpression of miR-127 maintains focal adhesion complex assembly and the integrity of tight junctions. miR-127 also regulates intracellular trafficking since miR-127 interference promotes dextran-FITC uptake. In fact, we have identified the Kinesin Family Member 3B (KIF3B), involved in cell trafficking, as a target of miR-127 in rat proximal tubule cells. In summary, we have described a novel role of miR-127 in cell adhesion and its regulation by HIF-1α. We also identified for the first time KIF3B as a miR-127 target. Both, miR-127 and KIF3B appear as key mediators of proximal epithelial tubule cell response to I/R with potential al application in renal ischemic damage management.

MicroRNA-489 Induction by Hypoxia–Inducible Factor–1 Protects against Ischemic Kidney Injury

“…In addition to the classic genes that facilitate oxygen delivery, angiogenesis, and anaerobic metabolism or glycolysis, 31,33 recent studies have documented HIF-1 regulation of miRs, such as miR-210, miR-21, miR-29, and miR-127. 25,[40][41][42] This study has further shown miR-489 induction via HIF-1. Importantly, by using anti-miR-489, we have shown a protective role of miR-489 in renal tubular cells, which may contribute to HIF-1-mediated regulation of ischemic AKI and kidney injury in general.…”

MicroRNA-24 Antagonism Prevents Renal Ischemia Reperfusion Injury

“…10 MiR-127 contributed to the severity of renal I/R injury through a modulation of cell trafficking. 11 However, none of the studies presented so far evaluated the protective potential of specific pharmacologic miRNA inhibition during renal I/R injury. We provide evidence of the in vivo relevance of miR-24 in human and murine renal I/R injury.…”

Roles of Non-Coding RNAs in Acute Kidney Injury

“…As shown in Table 1, a number of miRNAs, such as miR-21 [33], miR-24 [34], miR-30 family [35], miR-126 [36], miR-127 [37], miR-150 [38], miR-494 [39] and miR-687 [40], have been implicated in both protective and pathogenic roles in the development of AKI.…”

“…Microarrays and RT-PCR analysis in proximal tubule (PT) cells and in a rat renal I/R model have shown that expression of miR-127 is induced during I/R injury [37]. Subsequent analysis indicated that miR-127 could protect PT cells against I/R injury by targeting kinesin family member 3B (KIF3B) ( Figure 3C), a protein involved in cell trafficking [37].…”

“…Subsequent analysis indicated that miR-127 could protect PT cells against I/R injury by targeting kinesin family member 3B (KIF3B) ( Figure 3C), a protein involved in cell trafficking [37]. In vitro interference approaches demonstrated that HIF-1α regulates miR-127 in HK-2 cells in response to hypoxia/reoxygenation (H/R), although the binding site of HIF-1α has not been successfully identified [37].…”