Role of Autophagy on Heavy Metal-Induced Renal Damage and the Protective Effects of Curcumin in Autophagy and Kidney Preservation.

Curcumin is a hydrophobic polyphenol compound extracted from the rhizome of turmeric. The protective effect of curcumin on kidney damage in multiple experimental models has been widely described. Its protective effect is mainly associated with its antioxidant and anti-inflammatory properties, as well as with mitochondrial function maintenance. On the other hand, occupational or environmental exposure to heavy metals is a serious public health problem. For a long time, heavy metals-induced nephrotoxicity was mainly associated with reactive oxygen species overproduction and loss of endogenous antioxidant activity. However, recent studies have shown that in addition to oxidative stress, heavy metals also suppress the autophagy flux, enhancing cell damage. Thus, natural compounds with the ability to modulate and restore autophagy flux represent a promising new therapeutic strategy. Furthermore, it has been reported in other renal damage models that curcumin's nephroprotective effects are related to its ability to regulate autophagic flow. The data indicate that curcumin modulates autophagy by classic signaling pathways (suppression of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and/or by stimulation of adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-dependent kinase (ERK) pathways). Moreover, it allows lysosomal function preservation, which is crucial for the later stage of autophagy. However, future studies of autophagy modulation by curcumin in heavy metals-induced autophagy flux impairment are still needed.

Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although the effect of high glucose on liver function has been described, the role of MIF in hepatic mitochondrial function during T2DM has not been studied. OBJECTIVE: We examine the influence of MIF to hepatic mitochondrial function in T2DM mouse model. METHODS: WT and Mif-/- BALB/c mice were treated with a single dose of streptozotocin (STZ). After an 8-week follow-up, serum glucose, proinflammatory cytokines, C-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme quantification, and liver histological analyses were performed. Liver mitochondria were extracted, and mitochondrial function was evaluated by oximetry, swelling and peroxide production. RESULTS: Following treatment with STZ, WT mice (WT/STZ) developed significant hyperglycemia and high serum levels of MIF, tumor necrosis factor (TNF)-α, interleukin-ß (IL-ß), and CRP. Liver damage enzymes ALT and AST were found at high levels. In contrast, Mif-/-STZ lacked serum MIF levels and showed smaller increases in blood glucose, less TNF-α, IL-1ß, CPR, ALT and AST, and failure to develop clinical signs of disease compared to the WT/STZ group. Mitochondria extracted from the Mif-/-STZ liver showed similar respiratory control (RC) to WT/STZ or healthy mice with glutamate/malate or succinate as substrates. The four respiratory chain complexes also had comparable activities. WT/STZ-isolated mitochondria showed low swelling with calcium compared to mitochondria from Mif-/-STZ or healthy mice. Peroxide production was comparable in all groups. CONCLUSION: These results show although high systemic levels of MIF contribute to the development of T2DM pathology, the liver mitochondria remain unaltered. Importantly, the absence of MIF reduced the pathology of T2DM, also without altering liver mitochondrial function. These support MIF as a therapeutic target for the treatment of this disease in humans.