Abstract
Little is known about the effects of chronic alcohol intake on the outcome of acute kidney injury (AKI). Hence, we examined the effects of chronic alcohol intake on the development of renal fibrosis following AKI in an animal model of bilateral renal ischemia–reperfusion (IR) injury. We first found that chronic alcohol exposure exacerbated bilateral IR-induced renal fibrosis and renal function impairment. This phenomenon was associated with increased bilateral IR-induced extracellular matrix deposition and an increased myofibroblast population as well as increased bilateral IR-induced expression of fibrosis-related genes in the kidneys. To explore the mechanisms underlying this phenomenon, we showed that chronic alcohol exposure enhanced β-arrestin 2 (Arrb2) expression and Akt and glycogen synthase kinase-3 (GSK3)β activation in the kidneys. Importantly, pharmacological GSK3 inhibition alleviated bilateral IR-induced renal fibrosis and renal function impairment. Furthermore, we demonstrated that Arrb2−/− mice exhibited resistance to IR-induced renal fibrosis and renal function impairment following chronic alcohol exposure, and these effects were associated with attenuated GSK3β activation in the kidneys. Taken together, our results suggest that chronic alcohol exposure may potentiate AKI via β-arrestin 2/Akt/GSK3β-mediated signaling in the kidney.
Highlights
Acute kidney injury (AKI) is a major clinical problem that can result in prolonged hospitalization, chronic renal failure and death.[1,2,3,4,5] One of the leading causes of AKI is renal ischemia–reperfusion injury (IRI) due to surgical renal ischemia or renal hypoperfusion.[1,2] Importantly, evidence has shown that the severity and incidence of AKI have been increasing in recent years.[6]
We demonstrated that Arrb2− / − mice exhibited resistance to IR-induced renal fibrosis and renal function impairment following chronic alcohol exposure, and these effects were associated with attenuated GSK3β activation in the kidneys
We examined the effects of chronic alcohol intake on the development of renal fibrosis following AKI in an animal model of bilateral renal IRI
Summary
Acute kidney injury (AKI) is a major clinical problem that can result in prolonged hospitalization, chronic renal failure and death.[1,2,3,4,5] One of the leading causes of AKI is renal ischemia–reperfusion injury (IRI) due to surgical renal ischemia or renal hypoperfusion.[1,2] Importantly, evidence has shown that the severity and incidence of AKI have been increasing in recent years.[6]. The associations between high alcohol consumption and the progression of kidney damage such as chronic kidney disease (CKD) remain controversial,[7] it has been recognized that chronic alcohol intake can affect renal function. Alcoholic liver cirrhosis with associated hepato-renal syndrome is a common complication of chronic alcohol consumption and can result in renal failure because of extreme splanchnic vasodilatation and compensatory renal vasoconstriction.[8,9] In addition, evidence has suggested that a wide range of disturbances in electrolyte and acid–base balance can be observed in alcoholics because of alcoholinduced tubular dysfunction.[10,11,12,13] we hypothesized that a history of chronic alcohol intake may worsen the consequences of AKI. Renal IRI is a widely used animal model for the study of mechanisms underlying AKI. As a model of AKI, bilateral renal IRI can induce a significant increase in serum creatinine and blood urea nitrogen (BUN), which are seen in patients with AKI.[6,14] While some studies have examined the long-term impact of bilateral renal IRI,[15,16,17] most have indicated that kidney function and morphology can return to almost normal ~ 2 weeks after the initial mild bilateral renal IRI.[14,18,19]
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