title: Stabilization of endogenous Nrf2 by minocycline protects against Nlrp3-inflammasome induced diabetic nephropathy.
abstract: While a plethora of studies support a therapeutic benefit of Nrf2 activation and ROS inhibition in diabetic nephropathy (dNP), the Nrf2 activator bardoxolone failed in clinical studies in type 2 diabetic patients due to cardiovascular side effects. Hence, alternative approaches to target Nrf2 are required. Intriguingly, the tetracycline antibiotic minocycline, which has been in clinical use for decades, has been shown to convey anti-inflammatory effects in diabetic patients and nephroprotection in rodent models of dNP. However, the mechanism underlying the nephroprotection remains unknown. Here we show that minocycline protects against dNP in mouse models of type 1 and type 2 diabetes, while caspase -3,-6,-7,-8 and -10 inhibition is insufficient, indicating a function of minocycline independent of apoptosis inhibition. Minocycline stabilizes endogenous Nrf2 in kidneys of db/db mice, thus dampening ROS-induced inflammasome activation in the kidney. Indeed, minocycline exerts antioxidant effects in vitro and in vivo, reducing glomerular markers of oxidative stress. Minocycline reduces ubiquitination of the redox-sensitive transcription factor Nrf2 and increases its protein levels. Accordingly, minocycline mediated Nlrp3 inflammasome inhibition and amelioration of dNP are abolished in diabetic Nrf2-/-mice. Taken together, we uncover a new function of minocycline, which stabilizes the redox-sensitive transcription factor Nrf2, thus protecting from dNP.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.|University of Health Sciences, Khayaban-e-Jamia Punjab, 54600, Lahore, Pakistan.
authors.forename: Khurrum
authors.initials: K
authors.lastname: Shahzad
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.|Department of Medicine, Vanderbilt University Medical Center, 37232 Nashville, Tennessee, United States.
authors.forename: Fabian
authors.initials: F
authors.lastname: Bock
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
authors.forename: Moh'd Mohanad
authors.initials: MM
authors.lastname: Al-Dabet
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
authors.forename: Ihsan
authors.initials: I
authors.lastname: Gadi
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
authors.forename: Sumra
authors.initials: S
authors.lastname: Nazir
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.|Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
authors.forename: Shrey
authors.initials: S
authors.lastname: Kohli
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
authors.forename: Satish
authors.initials: S
authors.lastname: Ranjan
authors.affiliation: Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
authors.affiliation: Department of Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008911:Minocycline / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects
chemical_list: D058847:Inflammasomes; D051267:NF-E2-Related Factor 2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495636:Nfe2l2 protein, mouse; C492716:Nlrp3 protein, mouse; D008911:Minocycline