Involvement of renin–angiotensin–aldosterone system in calcium oxalate crystal induced activation of NADPH oxidase and renal cell injury

Hidenori Tsuji, Wei Wang, Joshi Sunil, Nobutaka Shimizu, Kazuhiro Yoshimura, Hirotsugu Uemura, Ammon B. Peck, Saeed R. Khan

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Introduction and objectives: Reactive oxygen species (ROS) are produced during the interaction between oxalate/calcium oxalate monohydrate (COM) crystals and renal epithelial cells and are responsible for the various cellular responses through the activation of NADPH oxidase (Nox). Ox and COM also activate the renin–angiotensin–aldosterone system (RAAS). Aldosterone stimulates ROS production through activation of Nox with the involvement of mineralocorticoid receptor (MR), Rac1 and mitogen-activated protein kinases (MAPK). We investigated RAAS pathways in vivo in an animal model of hyperoxaluria and in vitro by exposing renal epithelial cells to COM crystals. Methods: Hyperoxaluria was induced in male SD rats by administering ethylene glycol. One group of rats was additionally given spironolactone. Total RNA was extracted and subjected to genomic microarrays to obtain global transcriptome data. Normal rat kidney cell line (NRK-52E) was incubated with aldosterone(10−7 M) and COM(67 μg/cm2) with or without spironolactone(10−5 M), a selective inhibitor of SRC family of kinases; protein phosphatase 2(pp2) (10−5 M) and Nox inhibitor; diphenylene iodonium (DPI) (10−5 M). Results: Relative expression of genes encoding for AGT, angiotensin receptors 1b and 2, Renin 1, Cyp11b, HSD11B2, Nr3c2, NOx4 and Rac1 was upregulated in the kidneys of rats with hyperoxaluria. Treatment with spironolactone reversed the effect of hyperoxaluria. Both aldosterone and COM crystals activated Nox and Rac1 expression in NRK52E, while spironolactone inhibited Nox and Rac1 expression. Increased Rac1 expression was significantly attenuated by treatment with PP2 and spironolactone. Conclusions: Results indicate that hyperoxaluria-induced production of ROS, injury and inflammation are in part associated with the activation of Nox through renin–angiotensin–aldosterone pathway.

Original languageEnglish (US)
Pages (from-to)89-95
Number of pages7
JournalWorld Journal of Urology
Issue number1
StatePublished - Jan 1 2016
Externally publishedYes


  • Aldosterone
  • Mineralcorticoid receptor
  • NADPH oxidase
  • Rac1
  • Spironolactone

ASJC Scopus subject areas

  • Urology


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