Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis

Wenpeng Cui, Hasiyeti Maimaitiyiming, Xinyu Qi, Heather Norman, Qi Zhou, Xiaojun Wang, Jian Fu, Shuxia Wang

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Our previous studies support the protective effect of cGMP and cGMP-dependent protein kinase I (PKG-I) pathway on the development of renal fibrosis. Therefore, in the present studies, we determined whether pharmacologically or genetically increased PKG activity attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanisms involved. To increase PKG activity, we used the phosphodiesterase 5 inhibitor sildenafil and PKG transgenic mice. UUO model was induced in wild-type or PKG-I transgenic mice by ligating the left lateral ureteral and the renal fibrosis was observed after 14 days of ligation. Sildenafil was administered into wild-type UUO mice for 14 days. In vitro, macrophage and proximal tubular cell function was also analyzed. We found that sildenafil treatment or PKG transgenic mice had significantly reduced UUO-induced renal fibrosis, which was associated with reduced TGF-β signaling and reduced macrophage infiltration into kidney interstitial. In vitro data further demonstrated that both macrophages and proximal tubular cells were important sources of UUO-induced renal TGF-β levels. The interaction between macrophages and tubular cells contributes to TGF-β induced renal fibrosis. Taken together, these data suggest that increasing PKG activity ameliorates renal fibrosis in part through regulation of macrophage and tubular cell function, leading to reduced TGF-β-induced fibrosis.

Original languageEnglish
Pages (from-to)F996-F1007
JournalAmerican Journal of Physiology - Renal Physiology
Volume306
Issue number9
DOIs
StatePublished - May 1 2014

Keywords

  • PKG
  • Renal fibrosis
  • TGF-β1
  • UUO

ASJC Scopus subject areas

  • Physiology
  • Urology

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