Curcumin Attenuates Gentamicin-Induced Kidney Mitochondrial Alterations: Possible Role of a Mitochondrial Biogenesis Mechanism.

It has been shown that curcumin (CUR), a polyphenol derived from Curcuma longa, exerts a protective effect against gentamicin- (GM-) induced nephrotoxicity in rats, associated with a preservation of the antioxidant status. Although mitochondrial dysfunction is a hallmark in the GM-induced renal injury, the role of CUR in mitochondrial protection has not been studied. In this work, LLC-PK1 cells were preincubated 24 h with CUR and then coincubated 48 h with CUR and 8 mM GM. Treatment with CUR attenuated GM-induced drop in cell viability and led to an increase in nuclear factor (erythroid-2)-related factor 2 (Nrf2) nuclear accumulation and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) cell expression attenuating GM-induced losses in these proteins. In vivo, Wistar rats were injected subcutaneously with GM (75 mg/Kg/12 h) during 7 days to develop kidney mitochondrial alterations. CUR (400 mg/Kg/day) was administered orally 5 days before and during the GM exposure. The GM-induced mitochondrial alterations in ultrastructure and bioenergetics as well as decrease in activities of respiratory complexes I and IV and induction of calcium-dependent permeability transition were mostly attenuated by CUR. Protection of CUR against GM-induced nephrotoxicity could be in part mediated by maintenance of mitochondrial functions and biogenesis with some participation of the nuclear factor Nrf2.

C-phycocyanin prevents cisplatin-induced mitochondrial dysfunction and oxidative stress.

The potential of C-phycocyanin (C-PC) to prevent cisplatin (CP)-induced kidney mitochondrial dysfunction was determined in CD-1 male mice. The CP-induced mitochondrial dysfunction was characterized by ultrastructural abnormalities and by decrease in the following parameters in isolated kidney mitochondria: adenosine diphosphate (ADP)-induced oxygen consumption (state 3), respiratory control ratio, ADP/oxygen (ADP/O) ratio, adenosine triphosphate synthesis, membrane potential, calcium retention, glutathione (GSH) content, and activity of respiratory complex I, aconitase, catalase, and GSH peroxidase. These mitochondria also showed increase in hydrogen peroxide production, malondialdehyde, and 3-nitrotyrosine protein adducts content. The above-described changes, as well as CP-induced nephrotoxicity, were attenuated in mice pretreated with a single injection of C-PC. Our data suggest that the attenuation of mitochondrial abnormalities is involved in the protective effect of C-PC against CP-induced nephrotoxicity. This is the first demonstration that C-PC pretreatment prevents CP-induced mitochondrial dysfunction in mice.

Cardioprotection by curcumin post-treatment in rats with established chronic kidney disease.

PURPOSE: The pathogenic mechanisms leading to cardiovascular disorders in patients with chronic kidney disease have not been clearly established, although increased oxidative stress has been pointed out as a potential cause. Therefore, as cardiovascular events are still the first cause of death in patients with chronic kidney disease and traditional drugs or therapies rarely have effects on cardiac complications, we sought to determine the effect of curcumin in treating cardiac dysfunction in rats with established chronic renal disease. METHODS AND RESULTS: Treatment consisted in daily administration of curcumin (120 mg/kg/day) dissolved in 0.05% carboxymethylcellulose via oral gavages during 30 days, beginning from day 30 after 5/6 nephrectomy (5/6Nx). Cardiac function, markers of oxidative stress, activation of PI3K/Akt/GSK3ß and MEK1/2-ERK1/2 pathway, metalloproteinase-II (MMP-2) content, overall gelatinolytic activity, ROS production and mitochondrial integrity were evaluated after 1-month treatment. Curcumin restored systolic blood pressure, diminished interventricular and rear wall thickening, decreased left ventricle dimension at end-systole (LVSd) and restored ejection fraction in nephrectomized rats. Also, it diminished metalloproteinase-II levels and overall gelatinase activity, decreased oxidative stress and inhibited the mitochondrial permeability transition pore opening. CONCLUSION: Our findings suggest that curcumin might have therapeutic potential in treatment of heart disease in patients with established CKD by attenuating oxidative stress-related events as cardiac remodeling, mitochondrial dysfunction and cell death.

Mitochondria as a target in the therapeutic properties of curcumin.

Curcumin, a phenolic compound extracted from Curcuma longa, is commonly used in Asia as a spice and pigment and has several biological functions, particularly antioxidant properties. It has been reported that curcumin exhibits bifunctional antioxidant properties related to its capability to react directly with reactive oxygen species (ROS) and also to its ability to induce the expression of cytoprotective and antioxidant proteins through the transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2). Recently, it has been postulated that the mitochondrial function and metabolism are associated with Nrf2 and that curcumin has shown activities against mitochondrial dysfunction. The damage in mitochondria has been implicated in the pathogenesis of diseases like diabetes, cancer, aging, and neurodegenerative disorders. This review focuses on some of the most recent findings of curcumin properties that suggest a close relationship of this antioxidant with the mitochondrial function.

Curcumin attenuates Cr(VI)-induced ascites and changes in the activity of aconitase and F(1)F(0) ATPase and the ATP content in rat liver mitochondria.

Occupational and environmental exposure to potassium dichromate (K2Cr2O7), a hexavalent chromium compound, can result in liver damage associated with oxidative stress and mitochondrial dysfunction. The purpose of this study was to evaluate the effect of the antioxidant curcumin (400 mg/kg b.w.) on the K2Cr2O7-induced injury, with special emphasis on ascitic fluid accumulation and oxidative phosphorylation mitochondrial enzymes and the adenosine triphosphate (ATP) levels in isolated mitochondria from livers of rats treated with K2Cr2O7 (15 mg/kg b.w.). Thus, curcumin attenuated the ascites generation, prevented the decrease in the activities of aconitase and F1F0 ATPase, and maintained the ATP levels. The activity of complex II was not completely reestablished by curcumin, whereas complexes III and IV activities were unchanged.

Curcumin pretreatment prevents potassium dichromate-induced hepatotoxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening.

Curcumin is a polyphenol derived from turmeric with recognized antioxidant properties. Hexavalent chromium is an environmental toxic and carcinogen compound that induces oxidative stress. The objective of this study was to evaluate the potential protective effect of curcumin on the hepatic damage generated by potassium dichromate (K2Cr2O7) in rats. Animals were pretreated daily by 9-10 days with curcumin (400 mg/kg b.w.) before the injection of a single intraperitoneal of K2Cr2O7 (15 mg/kg b.w.). Groups of animals were sacrificed 24 and 48 h later. K2Cr2O7-induced damage to the liver was evident by histological alterations and increase in the liver weight and in the activity of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase in plasma. In addition, K2Cr2O7 induced oxidative damage in liver and isolated mitochondria, which was evident by the increase in the content of malondialdehyde and protein carbonyl and decrease in the glutathione content and in the activity of several antioxidant enzymes. Moreover, K2Cr2O7 induced decrease in mitochondrial oxygen consumption, in the activity of respiratory complex I, and permeability transition pore opening. All the above-mentioned alterations were prevented by curcumin pretreatment. The beneficial effects of curcumin against K2Cr2O7-induced liver oxidative damage were associated with prevention of mitochondrial dysfunction.

Curcumin maintains cardiac and mitochondrial function in chronic kidney disease.

Curcumin, a natural pigment with antioxidant activity obtained from turmeric and largely used in traditional medicine, is currently being studied in the chemoprevention of several diseases for its pleiotropic effects and nontoxicity. In chronic renal failure, the pathogenic mechanisms leading to cardiovascular disorders have been associated with increased oxidative stress, a process inevitably linked with mitochondrial dysfunction. Thus, in this study we aimed at investigating if curcumin pretreatment exerts cardioprotective effects in a rat model of subtotal nephrectomy (5/6Nx) and its impact on mitochondrial homeostasis. Curcumin was orally administered (120mg/kg) to Wistar rats 7 days before nephrectomy and after surgery for 60 days (5/6Nx+curc). Renal dysfunction was detected a few days after nephrectomy, whereas changes in cardiac function were observed until the end of the protocol. Our results indicate that curcumin treatment protects against pathological remodeling, diminishes ischemic events, and preserves cardiac function in uremic rats. Cardioprotection was related to diminished reactive oxygen species production, decreased oxidative stress markers, increased antioxidant response, and diminution of active metalloproteinase-2. We also observed that curcumin's cardioprotective effects were related to maintaining mitochondrial function. Aconitase activity was significantly higher in the 5/6Nx + curc (408.5±68.7nmol/min/mg protein) than in the 5/6Nx group (104.4±52.3nmol/min/mg protein, P<0.05), and mitochondria from curcumin-treated rats showed enhanced oxidative phosphorylation capacities with both NADH-linked substrates and succinate plus rotenone (3.6±1 vs 1.1±0.9 and 3.1±0.7 vs 1.2±0.8, respectively, P<0.05). The mechanisms involved in cardioprotection included both direct antioxidant effects and indirect strategies that could be related to protein kinase C-activated downstream signaling.

Protective effect of α-mangostin on cardiac reperfusion damage by attenuation of oxidative stress.

This study was designed to investigate if α-mangostin (α-M), a xanthone present in the pericarp of Garcinia mangostana L., was able to protect against reperfusion injury in Langendorff-reperfused hearts. It was observed that α-M maintains the cardiac mechanical work, diminishes the area of infarct, and prevents the decrease in cardiac ATP and phosphocreatine levels in the reperfused myocardium. The protective effect of this xanthone was associated with reduction of oxidative stress. α-M treatment prevented reperfusion injury-induced protein oxidation (protein carbonyl content), lipid peroxidation (malondialdehyde and 4-hydroxynonenal content), and diminution of glutathione content. In fact, after α-M treatment, the values in these parameters were comparable to those obtained in nonreperfused hearts. In summary, α-M induces a protective effect in postischemic heart associated to the prevention of oxidative stress secondary to reperfusion injury.