The nephroprotection exerted by curcumin in maleate‐induced renal damage is associated with decreased mitochondrial fission and autophagy

Abstract

We have previously reported that the antioxidant curcumin exerts nephroprotection in maleate-induced renal damage, a model associated with oxidative stress. However, the mechanisms involved in curcumin protective effect were not explored, to assess this issue, curcumin was administered daily by gavage (150 mg/kg) five days before a single maleate (400 mg/kg)-injection. Curcumin prevented maleate-induced proteinuria, increased heat shock protein of 72 KDa (Hsp72) expression, and decreased plasma glutathione peroxidase activity. Maleate-induced oxidative stress by increasing the nicotinamide-adenine dinucleotide phosphate oxidase 4 (NOX4) and mitochondrial complex I-dependent superoxide anion (O • ) production, formation of malondialdehyde (MDA)- and 3-nitrotyrosine (3-NT)-protein adducts and protein carbonylation and decreased GSH/GSSG ratio. Curcumin treatment ameliorated all the above-described changes. The maleate-induced epithelial damage, evaluated by claudin-2 and occludin expressions, was ameliorated by curcumin. It was found that maleate-induced oxidative stress promoted mitochondrial fission, evaluated by dynamin-related protein (Drp) 1 and fission (Fis) 1 expressions and by electron-microscopy, and autophagy, evaluated by phospho-threonine 389 from p70 ribosomal protein S6 kinase (p-Thr 389 p70S6K), beclin 1, microtubule-associated protein 1A/1B-light chain 3 phosphatidylethanolamine conjugate (LC3-II), autophagy-related gene 5 and 12 (Atg5-Atg12) complex, p62, and lysosomal-associated membrane protein (LAMP)-2 expressions in isolated proximal tubules and by electron-microscopy and LC-3 immunolabelling. Curcumin treatment ameliorated these changes. Moreover, curcumin alone induced autophagy in proximal tubules. These data suggest that the nephroprotective effect exerted by curcumin in maleate-induced renal damage is associated with decreased mitochondrial fission and autophagy. © 2016 BioFactors, 42(6):686-702, 2016.

Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction

“…37 Mitochondrial alterations have recently emerged as the principal cause for the development of several forms of acute kidney injury, especially those involving cell death promotion and inflammatory processes. [7][8][9][10][11][12][13] Although the role of mitochondria has been less studied in the case of CKD development, growing evidence suggests that renal mitochondrial alterations also play a primary role in the progression of several types of CKD. 38,39 Interestingly, fibrotic processes have been related to mitochondrial impairment, and this last one by itself also promotes kidney function deterioration in obstructive nephropathy, [40][41][42] suggesting that mitochondrial alterations could play a fundamental role in the pathology of CKD.…”

“…Mitochondrial dysregulation is especially involved in the progression of CKD by promoting fibrosis pathways. [7][8][9][10][11][12][13][40][41][42] In the case of the UUO model, the participation of mitochondria in the progression of the illness is less 1 day #MnSOD, number of mitochondria and cAMP 58,147 "GRP78, PERK, p-eIF2α, ATF4, ATF6. #sXBP1 147 3-5 days #MnSOD, CI-CV, Opa1, caspase 3, FIS1.…”

Oxidative Stress and Renal Fibrosis: Recent Insights for the Development of Novel Therapeutic Strategies

“…Recently, berberine was reported to activate Nrf2 nuclear translocation and inhibit apoptosis of renal tubular epithelial cells induced by high glucose (Zhang et al, 2016 ). Curcumin from Curcuma Longa L. has well-documented anti-oxidant and renoprotective actions in several animal models of kidney injury, including Rhabdomyolysis-induced AKI (Chen X. et al, 2017 ), maleate-induced renal injury (Molina-Jijon et al, 2016 ), streptozotocin-induced diabetes (Ho et al, 2016 ), and the rat remnant kidney (Tapia et al, 2013 ). Recent evidence indicates that curcumin and its derivatives are potent hydrogen donors and may thus act primarily as chain breaking antioxidants, as opposed to direct free radical scavengers (Morales et al, 2015 ).…”

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

“…On the other hand, curcumin administration has been able to restore renal function in several models of kidney damage [8,14,28,29]. Furthermore, in hyperoxaluria, maleate and contrast-induced nephropathy, curcumin’s nephroprotection has been related to its ability to modulate the autophagy flux [17,30,31]. However, curcumin’s effect on heavy metals-induced autophagy flux impairment has not been explored yet, generating the opportunity for exploration in future studies.…”