The role of the polyol pathway in acute kidney injury caused by hindlimb ischaemia in mice

Abstract

The polyol pathway, a collateral glycolytic process, previously considered to be active in high glucose milieu, has recently been proposed to play a crucial role in ischaemia/reperfusion tissue injury. In this study, we explored the role of the polyol pathway in acute kidney injury (AKI), a life-threatening condition, caused by hindlimb ischaemia, and determined if inhibition of the polyol pathway by aldose reductase (AR) inhibitor is beneficial for this serious disorder. Mice 8 weeks of age rendered hindlimb ischaemic for 3 h by the clipping of major supporting arteries revealed marked muscle necrosis with accumulation of sorbitol and fructose in ischaemic muscles. Serum concentrations of blood urea nitrogen (BUN), creatinine phosphokinase (CPK), creatinine, tumour necrosis factor (TNF)-alpha as well as interleukin (IL)-6 were all elevated in these mice. Treatment with AR inhibitor (ARI) effectively suppressed muscle necrosis and accompanying inflammatory reactions and prevented renal failure. Similar to ARI-treated mice, AR-deficient mice were protected from severe ischaemic limb injury and renal failure, showing only modest muscle necrosis and significant suppression of serum markers of renal failure and inflammation. Thus, these findings suggest that the polyol pathway is implicated in AKI caused by ischaemic limb injury and that AR may be a potential therapeutic target for this condition.

The inhibition of aldose reductase on mucus production induced by interleukin-13 in the human bronchial epithelial cells

“…The reduced GS-lipid aldehyde, GS-DHN, can activate the transcription factors and subsequent expression of inflammatory genes. ROS are the major cause of the formation of GS-DHN and the continuously formed GS-DHN results in more ROS generation by amplifying the inflammatory response [12][13][14][15][16][17][18][19]28]. We identified that treatment with zopolrestat or transfection with AR siRNA could effectively block increased levels of ROS generation induced by IL-13.…”

“…The reduced form of the glutathione conjugate of HNE (GS-DHN) could activate the inflammatory cascade and contribute to goblet cell hyperplasia [12][13][14][15]. AR has been regarded as an important enzyme in the regulation of molecular signaling cascade International Immunopharmacology 12 (2012) 588-593 that may activate oxidative stress-induced cytotoxic events [16][17][18][19]. Since ROS-mediated activation inflammatory cytokines are known to result in mucus hypersecretion and AR has been implicated in ROSmediated inflammation, we envisioned that AR inhibition could decrease mucus production in chronic inflammation lung disease.…”

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…Marked muscle necrosis and renal failure with accumulation of sorbitol and fructose were identified in ischaemic muscles of mice [17], and the disturbance in the renal medulla including oxygen tension, oxygen consumption, lactate/pyruvate ratio and pH were observed in diabetic rats [21]. Notably, these alterations were preventable by either ARI treatment or AR-deficient suggesting the involvement of the polyol pathway in the acute kidney injury.…”

“…Also, AR-deficient mice were protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage [16]. AR-deficient or ARI-treated mice were protected from severe ischaemic limb injury and renal failure, showing only modest muscle necrosis and significant suppression of serum markers of renal failure and inflammation [17]. In addition, AR inhibition counteracted diabetes-induced oxidativenitrosative stress and poly(ADP-ribose) polymerase activation in sciatic nerve and retina [18].…”

Chronology of mitochondrial and cellular events during skeletal muscle ischemia-reperfusion

“…A high level of K ϩ leads to cardiac dysfunction, whereas the release of myoglobin causes renal failure (47). Other factors are implied in multiple organ lesions after hindlimb I/R (199,200).…”