ABSTRACT
OBJECTIVES: Oxidative stress-mediated colistin's nephrotoxicity is associated with the diminished activity of nuclear factor erythroid 2-related factor 2 (Nrf2) that is primarily correlated with cellular PH domain and leucine-rich repeat protein phosphatase (PHLPP2) levels. This study investigated the possible modulation of PHLPP2/protein kinase B (Akt) trajectory as a critical regulator of Nrf2 stability by rosuvastatin (RST) to guard against colistin-induced oxidative renal damage in rats. METHODS: Colistin (300,000 IU/kg/day; i.p.) was injected for 6 consecutive days, and rats were treated simultaneously with RST orally at 10 or 20 mg/kg. KEY FINDINGS: RST enhanced renal nuclear Nrf2 translocation as revealed by immunohistochemical staining to boost the renal antioxidants, superoxide dismutase (SOD) and reduced glutathione (GSH) along with a marked reduction in caspase-3. Accordingly, rats treated with RST showed significant restoration of normal renal function and histological features. On the molecular level, RST effectively decreased the mRNA expression of PHLPP2 to promote Akt phosphorylation. Consequently, it deactivated GSK-3ß and reduced the gene expression of Fyn kinase in renal tissues. CONCLUSIONS: RST could attenuate colistin-induced oxidative acute kidney injury via its suppressive effect on PHLPP2 to endorse Nrf2 activity through modulating Akt/GSK3 ß/Fyn kinase trajectory.
Subject(s)
Acute Kidney Injury , Proto-Oncogene Proteins c-akt , Rats , Animals , Proto-Oncogene Proteins c-akt/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , NF-E2-Related Factor 2/metabolism , Rosuvastatin Calcium/pharmacology , Colistin/metabolism , Colistin/pharmacology , Signal Transduction , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3/pharmacology , Oxidative Stress , Antioxidants/pharmacology , Antioxidants/metabolism , Kidney , Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , Acute Kidney Injury/prevention & control , Proto-Oncogene Proteins c-fyn/metabolism , Proto-Oncogene Proteins c-fyn/pharmacologyABSTRACT
Although the beneficial role of microRNA has been investigated thoroughly, the reno-protective role of microRNA-205 (miR-205) against colistin-induced nephrotoxicity has not yet been tackled. Hence, our study sought to study the possible modulatory effect of rosuvastatin on miR-205 and its downstream target, Egl-9 family hypoxia-inducible factor 2 (EGLN2) to combat oxidative and endoplasmic reticulum (ER) stresses as pivotal contributors to colistin-associated renal injury. Rats were randomly divided into four groups; normal, colistin (300 000 IU/Kg/day; i.p), colistin pretreated with rosuvastatin (10 mg/kg; p.o) and colistin pretreated with rosuvastatin (20 mg/kg; p.o) for 6 successive days. Pretreatment with rosuvastatin attenuated renal injury induced by colistin and enhanced kidney function with a marked reduction in renal injury markers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Besides, rosuvastatin upregulated renal miR-205 expression and suppressed gene expression of EGLN2. In addition, it downregulated ER stress-related genes (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)) along with caspases 12 and 3. It also induced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as detected by immunohistochemical examination besides increased renal antioxidants, reduced glutathione, and superoxide dismutase. In conclusion, rosuvastatin triggered a series of protective mechanisms against colistin-induced nephrotoxicity through modulating miR-205 and EGLN2 expression. Rosuvastatin suppressed ATF4/ CHOP trajectory and activated the Nrf2 pathway to substantiate its antioxidant and anti-apoptotic capacities.
Subject(s)
Colistin , MicroRNAs , Rosuvastatin Calcium , Animals , Rats , Activating Transcription Factor 4/genetics , Activating Transcription Factor 4/metabolism , Antioxidants/pharmacology , Apoptosis , Colistin/toxicity , Endoplasmic Reticulum Stress , MicroRNAs/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Rosuvastatin Calcium/pharmacology , Transcription Factor 4/metabolism , Transcription Factor CHOP/genetics , Transcription Factor CHOP/metabolismABSTRACT
Hepatotoxicity and nephrotoxicity are important drawbacks of cisplatin. The objective of this study is to evaluate the ability of ambroxol in 2 different doses (35 and 70 mg/kg, i.p.) to protect liver and kidney from damage induced by a single dose of cisplatin (10 mg/kg, i.p.) in comparison with N-acetylcysteine (250 mg/kg, i.p.). Inflammatory, oxidative stress, and apoptotic biomarkers were investigated to show the influence of ambroxol on hepatotoxicity and nephrotoxicity. Ambroxol decreased the elevated activity of liver enzymes (aspartate aminotransferase and alanine aminotransferase) and kidney function tests (blood urea nitrogen and creatinine). Ambroxol mitigated cisplatin inflammatory damage by inhibition of tumor necrosis factor-α, interleukin-1ß, and nuclear factor kappa-B and elevation of nuclear factor erythroid 2-related factor 2. Moreover, ambroxol inhibited oxidative damage indicated by reduction of malondialdehyde and replenished the store of reduced glutathione likely by upregulating glutathione reductase and superoxide dismutase. Elevation of phosphorylated c-Jun N-terminal kinases (p-JNK) and phosphorylated extracellular signal-regulated kinase (p-ERK) were attenuated by ambroxol associated with a decrease in the expression of caspase-3; these results were consistent with histopathological results. These results recommend ambroxol to be co-administered with cisplatin in cancer patients to ameliorate liver and kidney damage, and this was confirmed by MTT assay.
