MiR-210 Protects Renal Cell Against Hypoxia-induced Apoptosis by Targeting HIF-1 Alpha

Li-Li Liu,Dahu Li,Yan-Zhao Zhou,Xin Huang,Ming-Gao Li,Yun-Ling He,Kui-Wu Wu,Sheng-Hui Gong,Ming Fan,Li-Ying Wu,Tong Zhao,Yong-Qi Zhao,Ling-Ling Zhu,Lun Xu

doi:10.2119/molmed.2017.00013

Abstract

The kidney is vulnerable to hypoxia-induced injury. One of the mechanisms underlying this phenomenon is cell apoptosis triggered by hypoxia-inducible factor-1- α (HIF-1α) activation. MicroRNA-210 (miR-210) is known to be induced by HIF-1α and can regulate various pathological processes, but its role in hypoxic kidney injury remains unclear. Here, in both rat systemic hypoxia and local kidney hypoxia models, we found miR-210 levels were upregulated significantly in injured kidney, especially in renal tubular cells. A similar increase was observed in hypoxia-treated human renal tubular HK-2 cells. We also verified that miR-210 can directly suppress HIF-1α expression by targeting the 3′ untranslated region of HIF-1α mRNA in HK-2 cells in severe hypoxia. Accordingly, miR-210 overexpression caused significant inhibition of the HIF-1α pathway and attenuated apoptosis caused by hypoxia, while miR-210 knockdown exerted the opposite effect. Taken together, our findings verify that miR-210 is involved in the molecular response in hypoxic kidney lesions in vivo and attenuates hypoxia-induced renal tubular cell apoptosis by targeting HIF-1α directly and suppressing HIF-1α pathway activation in vitro.

Highlights

Oxygen is a vital microenvironmental substrate for sustaining tissue homeostasis
A similar and more significant activation of the hypoxia-inducible factor-1-α (HIF-1α) pathway was observed in the local kidney hypoxia rat model when treated with the acute kidney injury operation (Figure 1B)
Obvious tubular injury was observed by periodic acid–Schiff (PAS) staining in the local kidney hypoxia group (Figure 2A), while remarkable TdT-mediated dUTP Nick-end Labeling (TUNEL)-positive apoptotic renal cells were found in both groups (Figure 2B, C)

Summary

Introduction

Oxygen is a vital microenvironmental substrate for sustaining tissue homeostasis. Many physiological and pathological conditions cause insufficiency in oxygen availability, or hypoxia, which can eventually lead to apoptosis if the hypoxia is severe [1,2]. Systemic hypoxia drives multiorgan damage, especially kidney injury [5,6,7]. Another kind of kidney hypoxic injury is caused by local hypoxia, in which oxygen sufficiency usually originates from a decreased renal or intrarenal blood supply [8]. Both kinds of kidney hypoxic lesion can lead to acute kidney injury (AKI), which is a common cause of in-hospital mortality [9]. As for the mechanism of hypoxic kidney injury, the excessive and sustaining activation of hypoxia-inducible factor-1-α (HIF-1α) was deemed a critical event [10,11,12]

Methods

Results

Discussion

Conclusion