Amage, loss of CA activity, and bicarbonate wasting in the TDF
Amage, loss of CA activity, and bicarbonate wasting in the TDF treated rats. These observations suggest that bicarbonate wasting may be due to the loss of CA activity. It is worthwhile to mention here that CA is an enzyme that is susceptible to inactivation by ROS and RNS [68]. As in our study we have shown that TDF administration results in increased oxidative stress, nitrosative stress and GSH depletion in the kidneys we propose that the loss of CA activity may be due to its inactivation by ROS /and RNS. Succinate dehydrogenase (SDH) is a key enzyme in the Krebs cycle the activity level of which shows the degree of the activity of mitochondria [69]. A decrease in succinate dehydrogenase activity indicates loss of inner mitochondrial membrane integrity. SDH functions not only in mitochondrial energy generation, but also has a role in oxygen sensing [70]. Its unique redox properties [71] confer SDH a specific function in superoxide handling. Along with ubiquinone, SDH is a crucial antioxidant enzyme in mitochondria controlling superoxide scavenging activity of the respiratory chain. When succinate-ubiquinone activity is inhibited, electrons that would normally transfer through the SDH -B subunit to the ubiquinone pool are instead transferred to O2 directly to produce ROS, mainly superoxide anion [72]. In the present study we observed a significant decrease in SDH activity in the TDF treated rat kidneys. This finding not only suggests loss of inner mitochondrial membrane integrity but also suggests that decreased SDH may contribute to increased ROS production and hence oxidant stress. In summary, the results of the present study PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/29045898 show that long term administration of TDF results in proximal tubular mitochondrial damage and proximal tubular dysfunction which manifest as Fanconi Syndrome. TDF induced proximal tubular damage and mitochondrial damage was accompanied by increase in oxidative stress markers and decrease in the antioxidant system namely reduced GSH, SOD, GPO, GR, and carbonic anhydrase. This suggests that the depletion of cellular anti-oxidants contribute to TDF induced damage to the proximal tubular mitochondria. SOD is the first line of defense against mitochondrially Procyanidin B1 site derived ROS (superoxide) and so decrease in MnSOD activity can have deleterious effects on the cell. Therefore, logistically overexpression of MnSOD or administration of SOD mimetics should beAbraham et al. Journal of Biomedical Science 2013, 20:61 http://www.jbiomedsci.com/content/20/1/Page 14 ofbeneficial in the prevention of TDF nephrotoxicity. We are currently investigating whether the administration of SOD mimetic – Mn (III) ortho N-butoxyethylpyridyl porphyrin (4.5 mg/kg body wt./day and 9 mg/kg body wt. per day ) protects against TDF nephrotoxicity. This compound was chosen for the study as it is a potent SOD mimetic and is less toxic compared with other SOD mimetics [73].Conclusion Tenofovir- induced mitochondrial damage and increased oxidative stress in the rat kidneys may be due to depletion of the antioxidant system particularly, the glutathione dependent system and MnSOD.Competing interests The authors declare that they have no competing interests. Authors’ contributions PA conceived the study, designed it, and drafted the manuscript. BI carried out the histological studies. HR carried out the biochemical assays and immunohistochemical procedures. All authors read and approved the final manuscript. Acknowledgments We would like to thank the Centre for.
