Sodium/calcium overload and Sirt1/Nrf2/OH-1 pathway are critical events in mercuric chloride-induced nephrotoxicity

Mercury (Hg), a significant toxic metal for nephrotoxicity, can be found in food (vegetable and seafood) and drinking water by contamination. Oxidative stress is involved in inorganic Hg-induced nephrotoxicity, but the Sirtuin1 (Sirt1)/Nrf2/OH-1 pathway and sodium (Na)/calcium (Ca) ions actions in mercuric chloride (HgCl₂)-induced nephrotoxicity remains unclear to date. In this study, Kunming mice were treated HgCl₂ (5 mg/kg) for 24 h to evaluate potential mechanism. Here, along with Sirt1 activation, pale kidney, hisologic conditions, typical apoptotic changes and TUNEL positive nuclei were observed under acute HgCl₂ exposure. Specifically, although HgCl₂ increased the expression of Nrf2, Keap1, OH-1 and NQO1, the mRNA levels of GSS, GCLC and GCLM showed no significant alterations in mice kidney. Moreover, mice exposed to HgCl₂ decreased the concentrations of Mg, K, P, Mn, Fe, Zn, and elevated Na, Ca, Cu and Se in kidney. It was also observed that HgCl₂ suppressed the ATPases (Na⁺-K⁺-ATPase, Ca²⁺-ATPase, Mg²⁺-ATPase and Ca²⁺-Mg²⁺-ATPase) activities and decreased the mRNA levels of Atp1a1, Atp1a2 in the kidney. Further study showed that HgCl₂ elevated Na⁺ concentrations by markedly increased the mRNA levels of Na⁺ transporter. The present study revealed that HgCl₂ induced Sirt1/Nrf2/OH-1 pathway activation while did not inhibit apoptosis in kidney of mice. Additionally, HgCl₂ regulates Na⁺ concentrations, which might create secondary disorders in absorption and excretion of other ions. Altogether we assume that Sirt1/Nrf2/Na⁺/Ca²⁺ pathway might be a potential therapeutic target for treating acute HgCl₂ induced nephrotoxicity.