Mefunidone attenuates tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction

PLoS One. 2015 Jun 4;10(6):e0129283. doi: 10.1371/journal.pone.0129283. eCollection 2015.

Abstract

Background: Inflammation has a crucial role in renal interstitial fibrosis, which is the common pathway of chronic kidney diseases. Mefunidone (MFD) is a new compound which could effectively inhibit the proliferation of renal fibroblasts in vitro. However, the overall effect of Mefunidone in renal fibrosis remains unknown.

Methods: Sprague-Dawley rats were randomly divided intro 6 groups: sham operation, unilateral ureteral obstruction (UUO), UUO/Mefunidone (25, 50, 100mg/kg/day) and UUO/PFD (500mg/kg/day). The rats were sacrificed respectively on days 3, 7, and 14 after the operation. Tubulointerstitial injury index, interstitial collagen deposition, expression of fibronectin (FN), α-smooth muscle actin (α-SMA), type I and III collagen and the number of CD3+ and CD68+ cells were determined. The expressions of proinflammatory cytokines, p-ERK, p-IκB, and p-STAT3 were measured in human renal proximal tubular epithelial cells of HK-2 or macrophages.

Results: Mefunidone treatment significantly attenuated tubulointerstitial injury, interstitial collagen deposition, expression of FN, α-SMA, type I and III collagen in the obstructive kidneys, which correlated with significantly reduced the number of T cells and macrophages in the obstructive kidneys. Mechanistically, Mefunidone significantly inhibited tumor necrosis factor-α (TNF-α-) or lipopolysaccharide (LPS)-induced production of proinflammatory cytokines. This effect is possibly due to the inhibition of phosphorylation of ERK, IκB, and STAT3.

Conclusion: Mefunidone treatment attenuated tubulointerstitial fibrosis in a rat model of UUO, at least in part, through inhibition of inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Collagen / metabolism
  • Disease Models, Animal
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibronectins / metabolism
  • Fibrosis
  • Humans
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / etiology*
  • Kidney Diseases / pathology
  • Kidney Diseases / physiopathology
  • Kidney Function Tests
  • Macrophages / drug effects
  • Macrophages / pathology
  • Male
  • Mice, Inbred BALB C
  • NF-kappa B / metabolism
  • Phosphorylation / drug effects
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Pyridones / pharmacology
  • Pyridones / therapeutic use*
  • Rats, Sprague-Dawley
  • STAT3 Transcription Factor / metabolism
  • Transforming Growth Factor beta1 / pharmacology
  • Ureteral Obstruction / complications*
  • Ureteral Obstruction / drug therapy*
  • Ureteral Obstruction / physiopathology

Substances

  • 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one
  • Fibronectins
  • NF-kappa B
  • Piperazines
  • Pyridones
  • STAT3 Transcription Factor
  • Transforming Growth Factor beta1
  • Collagen
  • Extracellular Signal-Regulated MAP Kinases

Grants and funding

This project was supported by: the Doctoral Foundation of the Ministry of Education of China (grant no. 20120162130001), the National Natural Science Foundation of China (grant no. 81273575), the National Natural Science Foundation of China (grant no. 21172268), the major new-drug developing fund of the National Science and Technology Foundation of China (2012ZX09103101), and the National Natural Science Foundation of China (grant no. 81300610). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.