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: Xuan Xiong, Wenjuan Mei, Yanyun Xie, Jishi Liu, Miaomiao Lu, Xiongqun Peng, Congyin Yang, Xin Zhang, Mingyan Xie, Renna Luo, Xiangning Yuan, Ling Huang, Lin Wu, Jiao Qin, Yu Peng, Xiujie Jia, Gaoyun Hu, Damu Tang, Lijian Tao
• Journal: PloS one (PLoS One) Vol. 9 Issue 10 Pg. e111242 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25347392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone
• Blood Glucose
• Blood Proteins
• Pyridones
• Transforming Growth Factor beta
• Cholesterol
• NADPH Oxidases
• Proto-Oncogene Proteins c-akt
• protein kinase C zeta
• Protein Kinase C
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Blood Glucose (metabolism)
• Blood Proteins (metabolism)
• Cholesterol (blood)
• Diabetic Neuropathies (drug therapy)
• Kidney (drug effects, metabolism)
• Male
• Mice
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• NADPH Oxidases (metabolism)
• Protein Kinase C (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridones (pharmacology, therapeutic use)
• Transforming Growth Factor beta (metabolism)