Abstract
BackgroundRenal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury and a frequent occurrence in critically ill patients. Renal IRI releases proinflammatory cytokines within the kidney that induce crosstalk between the kidney and other organ systems. Atrial natriuretic peptide (ANP) has anti-inflammatory as well as natriuretic effects and serves important functions as a regulator of blood pressure, fluid homeostasis, and inflammation. The objective of the present study was to elucidate whether ANP post-treatment attenuates kidney-lung-heart crosstalk in a rat model of renal IRI.MethodsIn experiment I, a rat model of unilateral renal IRI with mechanical ventilation was prepared by clamping the left renal pedicle for 30 min. Five minutes after clamping, saline or ANP (0.2 μg/kg/min) was infused. The hemodynamics, arterial blood gases, and plasma concentrations of lactate and potassium were measured at baseline and at 1, 2, and 3 h after declamping. The mRNA expression and localization of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the kidney, lung, and heart were examined. In experiment II, a rat model of bilateral renal IRI without mechanical ventilation was prepared by clamping bilateral renal pedicles for 30 min. Thirty minutes after clamping, lactated Ringer's (LR) solution or ANP (0.2 μg/kg/min) was infused. Plasma concentrations of TNF-α, IL-6, and IL-1β were determined at baseline and at 3 h after declamping.ResultsIn unilateral IRI rats with mechanical ventilation, ANP inhibited the following changes induced by IRI: metabolic acidosis; pulmonary edema; increases in lactate, creatinine, and potassium; and increases in the mRNA expression of TNF-α, IL-1β, and IL-6 in the kidney and lung and IL-1β and IL-6 in the heart. It also attenuated the histological localization of TNF-α, IL-6, and nuclear factor (NF)-κB in the kidney and lung. In bilateral IRI rats without mechanical ventilation, ANP attenuated the IRI-induced increases of the plasma concentrations of potassium, IL-1β, and IL-6.ConclusionsRenal IRI induced injury in remote organs including the lung and the contralateral kidney. ANP post-treatment ameliorated injuries in these organs by direct tissue protective effect and anti-inflammatory effects, which potentially inhibited inter-organ crosstalk.
Highlights
Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury and a frequent occurrence in critically ill patients
Cytokine mRNA expression in the kidney, lung, and heart Unilateral IRI significantly increased the mRNA expressions of tumor necrosis factor-α (TNF-α), IL-6, and IL-1β in both the ipsilateral kidney (p < 0.05 for IL-6; p < 0.01 for tumor necrosis factor (TNF)-α and IL-1β) and the contralateral kidney (p < 0.01 for TNF-α, IL-6, and IL-1β)
IRI significantly increased the mRNA expressions of TNF-α, IL-1β, and IL-6 in the lung (p < 0.01, Figure 4) and those of IL-1β and IL-6 in the heart (p < 0.01, Figure 4), and Atrial natriuretic peptide (ANP) prevented these elevations in the expression of the transcripts of proinflammatory cytokines in these remote organs (Figure 4)
Summary
Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury and a frequent occurrence in critically ill patients. The objective of the present study was to elucidate whether ANP post-treatment attenuates kidney-lung-heart crosstalk in a rat model of renal IRI. Our hypothesis of experiment I is that unilateral renal IRI induces inflammation on the contralateral kidney as well as remote organs and ANP posttreatment attenuates kidney-lung crosstalk by inhibiting expanding inflammation. We examined the effects of IRI-induced inflammation on the contralateral kidney, lung, and heart in a rat model of unilateral renal IRI with mechanical ventilation and elucidated whether ANP post-treatment attenuates inter-organ crosstalk among the kidney, lung, and heart by inhibiting inflammation. Our hypothesis of experiment II is that bilateral renal IRI induces kidney injury accompanied by increase in circulating cytokines and ANP post-treatment attenuates release of cytokines from the kidney into circulation. We determined plasma cytokine concentration in the rat model of bilateral renal IRI excluding the effects of mechanical ventilation and saline and elucidated the inhibitory effect of ANP post-treatment on spreading inflammation
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