Overexpression of Heme Oxygenase-1 Prevents Renal Interstitial Inflammation and Fibrosis Induced by Unilateral Ureter Obstruction

PLoS One. 2016 Jan 14;11(1):e0147084. doi: 10.1371/journal.pone.0147084. eCollection 2016.

Abstract

Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases. Many studies have demonstrated that heme oxygenase-1 (HO-1) is involved in diverse biological processes as a cytoprotective molecule, including anti-inflammatory, anti-oxidant, anti-apoptotic, antiproliferative, and immunomodulatory effects. However, the mechanisms of HO-1 prevention in renal interstitial fibrosis remain unknown. In this study, HO-1 transgenic (TG) mice were employed to investigate the effect of HO-1 on renal fibrosis using a unilateral ureter obstruction (UUO) model and to explore the potential mechanisms. We found that HO-1 was adaptively upregulated in kidneys of both TG and wild type (WT) mice after UUO. The levels of HO-1 mRNA and protein were increased in TG mice compared with WT mice under normal conditions. HO-1 expression was further enhanced after UUO and remained high during the entire experimental process. Renal interstitial fibrosis in the TG group was significantly attenuated compared with that in the WT group after UUO. Moreover, overexpression of HO-1 inhibited the loss of peritubular capillaries. In addition, UUO-induced activation and proliferation of myofibroblasts were suppressed by HO-1 overexpression. Furthermore, HO-1 restrained tubulointerstitial infiltration of macrophages and regulated the secretion of inflammatory cytokines in UUO mice. We also found that high expression of HO-1 inhibited reactivation of Wnt/β-catenin signaling, which could play a crucial role in attenuating renal fibrosis. In conclusion, these data suggest that HO-1 prevents renal tubulointerstitial fibrosis possibly by regulating the inflammatory response and Wnt/β-catenin signaling. This study provides evidence that augmentation of HO-1 levels may be a therapeutic strategy against renal interstitial fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Proliferation
  • Disease Models, Animal
  • Fibrosis
  • Gene Expression Regulation
  • Gene Expression*
  • Heme Oxygenase-1 / genetics*
  • Mice
  • Myofibroblasts / metabolism
  • Nephritis, Interstitial / etiology*
  • Nephritis, Interstitial / pathology*
  • Up-Regulation
  • Ureteral Obstruction / complications*
  • Wnt Signaling Pathway

Substances

  • Heme Oxygenase-1

Grants and funding

This study was supported by research grants from the National Natural Science Foundation of China (No. 81370812), the National Basic Research Program of China 973 Program (No. 2012CB517602), the Doctoral Program of the Ministry of Education of China (20122307110018), the Special Grade of China Postdoctoral Science Foundation (No. 201003463), the Heilongjiang Postdoctoral Science Research Foundation (No. LBHQ10028), and the Heilongjiang Undergraduate Innovation Program (201310226036).