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Abstract
Previous studies suggest that 12/15 lipoxygenase (12/15-LO) is implicated in diabetic vascular complications. We hypothesize that 12/15-LO inhibition attenuates renal inflammation and injury in streptozotocin-induced diabetes. Diabetes was induced in wild-type C57BL/6J (WT) and 12/15-LO deficient mice using streptozotocin. Additionally, four groups of WT mice were also used; control non diabetic, diabetic, diabetic treated with the 12/15-LO inhibitor baicalein for 10 weeks and diabetic treated with baicalein only for the last 4 weeks of the experiment. After 10 weeks of induction of diabetes with streptozotocin, WT diabetic mice exhibited marked elevation in proteinuria together with elevation in the excretion levels of thiobarbituric acid reactive substance (TBARs), a marker of oxidative stress, and monocyte chemoattractant protein-1 (MCP-1), a marker of inflammation and these changes were significantly reduced in 12/15-LO deficient diabetic mice (P<0.05). Similarly, pharmacological inhibition of 12/15-LO with baicalein prevented the elevation in renal 12-HETE production, the major murine metabolic product of 12/15-LO, in diabetic mice, and this effect was associated with decreased proteinuria, TBARs excretion and renal collagen deposition compared to untreated diabetic mice. Interestingly, the protective effects of baicalein were not noticed when only administered in the last 4 weeks of diabetes compared to untreated diabetic mice. WT diabetic mice displayed elevation in renal interleukin-6 (IL-6) levels and these changes were only reduced in diabetic mice treated with baicalein for 10 weeks (P<0.05). The anti-inflammatory effects of baicalein or 12/15-LO deficiency were further confirmed in lipopolysaccharide (LPS)-induced acute renal inflammation as inhibition of 12/15-LO reduced the elevation in renal soluble epoxide hydrolase expression in LPS-injected mice. These results suggest that increased 12/15-LO activity and 12-HETE production contribute to the elevation of renal oxidative stress, inflammation and injury in streptozotocin-induced diabetic mice.
Highlights
The World Health Organization estimates that diabetes causes approximately five percent mortality worldwide and expects that number to double before the year 2030 without drastic changes in the treatment options
Proper control of blood glucose levels reduces the risk of diabetic nephropathy (DN); new therapeutic strategies are required to prevent the incidence of early diabetic renal injury and counteract the expected progression to end-stage renal disease and dialysis among the rapidly expanding diabetic population
The streptozotocin-injected wild-type C57BL/6J (WT) mice displayed a decrease (~18%; p
Summary
The World Health Organization estimates that diabetes causes approximately five percent mortality worldwide and expects that number to double before the year 2030 without drastic changes in the treatment options. Up to twenty percent of death is a result of end-stage renal disease, which is preceded by diabetic nephropathy (DN) [1]. The progression of DN manifests itself symptomatically via impairment in the glomerular filtration barrier resulting in microalbuminuria. This evolves into more devastating complications including hypertension, progressive injury of the glomerular structure and thickening of the glomerular basement membrane, increased collagen deposition and macroalbuminuria [2,3,4]. The elevation in renal macrophage infiltration is associated with changes in glomerular filtration rate together with increased intercellular adhesion molecule-1 (ICAM-1) and MCP-1 to direct their attachment to the site of inflammation [7,8]. It would fall to logic, that interference in these processes will attenuate the progression of renal injury in diabetic patients
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