title: Fluorofenidone offers improved renoprotection at early interventions during the course of diabetic nephropathy in db/db mice via multiple pathways.
abstract: Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease (ESRD), a situation that is in part attributable to the lack of effective treatments. Fluorofenidone is a newly developed reagent with anti-fibrotic activity. While fluorofenidone was previously demonstrated to possess renoprotection from DN pathogenesis in db/db mice, the protective process and its underlying mechanisms have not been well studied. To characterize fluorofenidone-derived renoprotection, we treated 5, 8, or 12-week old db/db mice with daily doses of placebo, fluorofenidone, or losartan until 24 weeks of age; the time at which diabetes and DN were fully developed in placebo-treated animals. In comparison to db/db mice receiving fluorofenidone at 12-weeks old, those treated at 5-weeks had less glomerular expansion and better preservation of renal functions, judged by serum creatinine levels, albumin to creatinine ratio, and urinary albumin excretion (mg/24 hours). These benefits of early treatment were associated with significant reductions of multiple DN-promoting events, such as decreased expression of TGF-β1 and the p22phox subunit of NADPH oxidase as well as downregulated activation of protein kinase C-zeta (ζ), ERK and AKT. This improvement in renoprotection following early interventions is not a unique property of DN pathogenesis, as losartan does not apparently offer the same benefits and is not more renoprotective than fluorofenidone. Additionally, the enhanced renoprotection provided by fluorofenidone did not affect the diabetic process, as it did not alter serum levels of glycated serum proteins, glucose, triglyceride or cholesterol. Collectively, we provide evidence that fluorofenidone offers improved renoprotection at early stages of DN pathogenesis.
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Mei
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Nephrology, The Third Xiangya Hospital, Changsha, Hunan, China.
authors.forename: Jishi
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Xiangya Hospital, Changsha, Hunan, China.
authors.forename: Xiongqun
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Gastroenterology, Xiangya Hospital, Changsha, Hunan, China.
authors.forename: Congyin
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Xiangya Hospital, Changsha, Hunan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Xiangya Hospital, Changsha, Hunan, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Xie
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Renna
authors.initials: R
authors.lastname: Luo
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Qin
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Respiratory Medicine, The second Xiangya Hospital, Changsha, Hunan, China.
authors.forename: Xiujie
authors.initials: X
authors.lastname: Jia
authors.affiliation: Chemistry Section, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Gaoyun
authors.initials: G
authors.lastname: Hu
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China; State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D001786:Blood Glucose; D001798:Blood Proteins; D002784:Cholesterol; D020929:Mitogen-Activated Protein Kinase Kinases; D019255:NADPH Oxidases; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D016212:Transforming Growth Factor beta; D000099221:Protein Kinase C zeta; C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone