Cross‐talk between micro RNA s, nuclear factor E 2‐related factor 2, and heme oxygenase‐1 in ochratoxin A ‐induced toxic effects in renal proximal tubular epithelial cells

Scope Ochratoxin A ( OTA ) is a mycotoxin exhibiting nephrotoxic and potential carcinogenic activity. We investigated the cross‐talk between micro RNA s, nuclear factor E 2‐related factor 2 ( N rf2), and heme oxygenase‐1 ( HO ‐1) in ochratoxin A ‐mediated effects. Methods and results In porcine renal proximal tubular cells, OTA increased expression of profibrotic transforming growth factors β ( TGF β) while concomitantly decreasing expression of N rf2, HO ‐1, and erythropoietin. Adenoviral overexpression of N rf2 counteracted OTA ‐mediated reduction in HO ‐1 and erythropoietin expression and cell proliferation as well as increase in reactive oxygen species ( ROS ) generation and TGF β expression. Additionally, inhibition of HO activity enhanced whereas adenoviral overexpression of HO ‐1 reduced expression of TGF β. Moreover, antioxidants, N ‐acetyl‐cysteine and desferioxamine, prevented OTA ‐mediated enhancement of ROS generation, and TGF β expression. Finally, OTA modulated micro RNA processing by upregulating LIN eage protein 28 and D i G eorge syndrome critical region‐8, increasing the total pool of cellular micro RNA s and elevating the expression of mi R ‐132 and mi R ‐200c. Inhibition of mi R ‐132 by specific antagomir restored the OTA ‐driven reduction in N rf2 expression. Moreover, anti‐mi R ‐132 and anti‐mi R ‐200c counteracted OTA ‐mediated decrease in HO ‐1 levels as well as increase in ROS production and TGF β expression. Conclusion We showed that attenuation of N rf2 and HO ‐1 expression through induction of mi R ‐132 and mi R ‐200c by OTA elevates ROS levels and profibrotic TGF β expression.