Limb ischemic preconditioning ameliorates renal microcirculation through activation of PI3K/Akt/eNOS signaling pathway after acute kidney injury

Cheng Chen,Xiaoping Li,Ran Jing,Yushang Tang,Wanfen Zhang,Li Sun,Tongqiang Liu

doi:10.1186/s40001-020-00407-4

Abstract

PurposeContrast-induced acute kidney injury (CI-AKI) resulting from administration of iodinated contrast media (CM) is the third leading cause of hospital-acquired acute kidney injury and is associated with substantial morbidity and mortality. Deteriorated renal microcirculation plays an important role in CI-AKI. Limb ischemic preconditioning (LIPC), where brief and non-injurious ischemia/reperfusion is applied to a limb prior to the administration of the contrast agent, is emerging as a promising strategy for CI-AKI prevention. However, it is not known whether the renal protection of LIPC against CI-AKI is mediated by regulation of renal microcirculation and the molecular mechanisms remain largely unknown.MethodsIn this study, we examined the renal cortical and medullary blood flow in a stable CI-AKI model using 5/6-nephrectomized (NE) rat. The LIPC and sham procedures were performed prior to the injection of CM. Furthermore, we analyzed renal medulla hypoxia using in vivo labeling of hypoxyprobe. Pharmacological inhibitions and western blotting were used to determine the underlying molecular mechanisms.ResultsIn this study, we found LIPC significantly ameliorated CM-induced reduction of medullary blood flow and attenuated CM-induced hypoxia. PI3K inhibitor (wortmannin) treatment blocked the regulation of medullary blood flow and the attenuation of hypoxia of LIPC. Phosphorylation of Akt/eNOS was significantly decreased via wortmannin treatment compared with LIPC. Nitric oxide synthase-inhibitor [Nω-nitro-l-arginine methyl ester (L-NAME)] treatment abolished the above effects and decreased phosphorylation of eNOS, but not Akt.ConclusionsCollectively, the results demonstrate that LIPC ameliorates CM-induced renal vasocontraction and is mediated by activation of PI3K/Akt/eNOS signaling pathway.

Highlights

With the increasing use of iodinated contrast medium (CM) in diagnostic and interventional procedures, CM-induced acute kidney injury (CI-AKI) has become the third most common cause for hospital-acquired AKI [1]
Collectively, the results demonstrate that Limb ischemic preconditioning (LIPC) ameliorates CM-induced renal vasocontraction and is mediated by activation of PI3K/Akt/Endothelial nitric oxide synthase (eNOS) signaling pathway
Compared with CM + Sham group, we found that LIPC significantly ameliorated CM-induced reduction of medullary blood flow, but not cortical blood flow, 10 min after CM administration (Fig. 1a, b)

Summary

Introduction

With the increasing use of iodinated contrast medium (CM) in diagnostic and interventional procedures, CM-induced acute kidney injury (CI-AKI) has become the third most common cause for hospital-acquired AKI [1]. The development of CI-AKI is associated with increased morbidity, prolonged hospitalization, cardiovascular events, persistent kidney damage and. The prophylactic strategies developed to mitigate CI-AKI are largely restricted to pre- and post-hydration protocols and attempts of pharmacological interventions have been disappointing [3]. The pathophysiology of CI-AKI is complex and far from being elucidated; two major pivotal factors are recognized: (1) vasoconstriction and renal ischemic injury; (2) renal tubular cytotoxicity [4, 5]. Iodinated contrast agent and oxygen-free radical have direct cytotoxic effects, which mediate direct tubular injury, inducing vacuolization, change in mitochondrial function, and even apoptosis [7]

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