Inhibition of 12/15-Lipoxygenase Reduces Renal Inflammation and Injury in Streptozotocin-Induced Diabetic Mice

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.

Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD2 in the kidney

“…ALOX15 is involved in chronic diseases, such as atherosclerosis, and its deletion in animal disease models improves these diseases [ 5 ]. Regarding the association of ALOX15 with renal disease, proteinuria is decreased in Alox15 −/− mice under glomerular injury by a streptozotocin-induced diabetic nephropathy model [ 37 ]. However, this diabetes mellitus mouse model does not show any decline in kidney function; thus, the mechanism on how ALOX15 is associated with impaired kidney function in CKD models has remained unclear.…”

Arachidonic Acid Metabolism and Kidney Inflammation

“…According to the current results, the effect of lox-related drugs in regulating inflammation is still in the experimental study stage. Baicalein, a 12/15-LOX inhibitor, was demonstrated to prevent the elevation in renal 12-HETE production and reduce renal inflammation in strptozotocin-induced diabetic mice [202].…”

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