title: 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.
authors.affiliation: Department of Oral Biology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Faulkner
authors.affiliation: Department of Oral Biology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Chelsey
authors.initials: C
authors.lastname: Pye
authors.affiliation: Department of Oral Biology, Georgia Regents University, Augusta, GA, USA; Department of Ophthalmology and Culver Vision Discovery Institute, Georgia Regents University, Augusta, GA, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Al-Shabrawey
authors.affiliation: Department of Oral Biology, Georgia Regents University, Augusta, GA, USA; Department of Pharmacology & Toxicology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Elmarakby
keywords: 12/15-LO Deficient mice; Baicalein; Diabetes; Inflammation; Kidney; Oxidative stress; Proteinuria
references.citation: Prim Care Diabetes. 2014 Jul;8(2):159-63
references.pmid: 24332548
references.citation: Physiol Rev. 2013 Jan;93(1):137-88
references.pmid: 23303908
references.citation: Diabetes Metab J. 2014 Aug;38(4):252-60
references.pmid: 25215271
references.citation: Arterioscler Thromb Vasc Biol. 2004 Sep;24(9):1542-8
references.pmid: 15166011
references.citation: Nephron Exp Nephrol. 2005;100(3):e113-23
references.pmid: 15824514
references.citation: J Biol Chem. 1982 Sep 10;257(17):10294-9
references.pmid: 6809747
references.citation: Arterioscler Thromb Vasc Biol. 1999 Nov;19(11):2615-22
references.pmid: 10559003
references.citation: Kidney Int. 2006 Feb;69(3):512-9
references.pmid: 16514433
references.citation: J Am Soc Nephrol. 2003 Dec;14(12):3178-87
references.pmid: 14638916
references.citation: Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E175-87
references.pmid: 20978234
references.citation: Apoptosis. 2014 Apr;19(4):567-80
references.pmid: 24248985
references.citation: Int J Biochem Cell Biol. 2013 Aug;45(8):1620-8
references.pmid: 23685077
references.citation: J Am Soc Nephrol. 1997 Mar;8(3):487-93
references.pmid: 9071718
references.citation: Exp Neurol. 2011 Jul;230(1):106-13
references.pmid: 21515260
references.citation: Prostaglandins Other Lipid Mediat. 2003 Jul;71(3-4):189-204
references.pmid: 14518561
references.citation: Am J Physiol Renal Physiol. 2008 Aug;295(2):F605-17
references.pmid: 18562637
references.citation: Crit Care. 2012 Sep 13;16(5):R166
references.pmid: 22973824
references.citation: Mol Cell Endocrinol. 2012 Oct 15;362(1-2):128-38
references.pmid: 22698522
references.citation: J Exp Med. 2006 Oct 30;203(11):2529-40
references.pmid: 17043146
references.citation: J Biol Chem. 2013 Oct 4;288(40):28668-86
references.pmid: 23940049
references.citation: Semin Nephrol. 2010 May;30(3):290-301
references.pmid: 20620673
references.citation: J Immunol. 2009 Oct 1;183(7):4715-22
references.pmid: 19752233
references.citation: Endocrinology. 2007 Mar;148(3):1313-22
references.pmid: 17170102
references.citation: Kidney Int. 2014 Jul;86(1):50-7
references.pmid: 24717301
references.citation: Am J Physiol Regul Integr Comp Physiol. 2012 Feb 1;302(3):R321-30
references.pmid: 22116511
references.citation: Diabetologia. 2008 Jan;51(1):198-207
references.pmid: 17968528
references.citation: Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):4947-51
references.pmid: 8506339
references.citation: Diabetes. 2003 Oct;52(10):2586-93
references.pmid: 14514644
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2005 Jan;72(1):13-20
references.pmid: 15589395
references.citation: Kidney Int. 1999 Aug;56(2):393-405
references.pmid: 10432377
references.citation: Invest Ophthalmol Vis Sci. 2009 May;50(5):2319-27
references.pmid: 19011009
references.citation: Biochimie. 2014 Nov;106:101-10
references.pmid: 25151412
references.citation: Am J Physiol Renal Physiol. 2013 Sep 1;305(5):F691-700
references.pmid: 23804455
references.citation: J Diabetes Complications. 2003 Jan-Feb;17(1):11-5
references.pmid: 12505750
references.citation: Pharmacol Biochem Behav. 2010 Oct;96(4):469-75
references.pmid: 20637223
references.citation: Nephrol Dial Transplant. 2004 Dec;19(12):2987-96
references.pmid: 15574996
references.citation: Am J Physiol. 1997 Nov;273(5 Pt 2):H2224-31
references.pmid: 9374757
references.citation: Clin Med (Lond). 2013 Oct;13(5):460-4
references.pmid: 24115702
references.citation: J Lipid Res. 2015 Mar;56(3):599-611
references.pmid: 25598081
references.citation: Kidney Int. 2001 Apr;59(4):1354-62
references.pmid: 11260396
references.citation: Diabetologia. 2013 May;56(5):1166-73
references.pmid: 23412605
references.citation: J Clin Endocrinol Metab. 1996 May;81(5):1940-5
references.pmid: 8626861
references.citation: World J Diabetes. 2014 Jun 15;5(3):393-8
references.pmid: 24936261
references.citation: PLoS One. 2013;8(2):e57254
references.pmid: 23437353
references.citation: Adv Exp Med Biol. 1989;259:49-74
references.pmid: 2696359
references.citation: Horm Metab Res. 2006 Jun;38(6):391-6
references.pmid: 16823721