الفهرس 
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Abstract
Acute kidney injury is a clinical syndrome with a high morbidity and mortality rates. Cisplatin the drug that is widely used to treat a variety of tumors has been postulated to induce nephrotoxicity through triggering the apoptosis of tubular cells. Recently AD-MSCs have been suggested as a potentially useful therapeutic strategy in various diseases, including acute kidney injury. All-trans retinoic acid (ATRA) is the biological active metabolite of vitamin A (all-trans-retinol), it has reported to induce the proliferation, potentiation and migration capacity of MSCs, as well as its other roles such as anti-oxidant (act as scavenger of free radicals), anti- inflammatory, and anticancer effects (by acting as anti-proliferative for cancer cells). Aim of the work: The aim of this study was to investigate the therapeutic potential of adipose derived mesenchymal stem cells (AD-MSCs) in the treatment of acute kidney injury induced by cisplatin, as well as the enhancing effect of ATRA on AD-MSCS and their effects on kidney functions.
Subjects and Methods: The study included one hundred and twenty six rats were divided into 7 groups, group I (Negative control group) (N=18): Eighteen normal rats were injected intraperitoneally (I.P) with 1 ml saline only, group II (DMSO group) (N=18): eighteen normal rats were injected intraperitoneally with 1 ml DMSO (the vehicle of all-trans retinoic acid), group III (Culture media group) (N=18): eighteen normal rats were injected intravenously (I.V) through the tail vein with 0.2 ml culture media, group IV (Cisplatin group) (N=18): eighteen normal rats were injected intraperitoneally with cisplatin (6 mg/Kg body weight), group V (Cisplatin and ATRA group) (N=18): eighteen normal rats were injected intravenously with 10µM (0.01M) ATRA after one day of cisplatin injection, group VI (Cisplatin and Stem cells group) (N=18): eighteen normal rats were injected intravenously with 0.2 ml culture media containing 1 × 106 MSCs after one day of cisplatin injection, and group VII (Cisplatin, ATRA, and MSCs group) (N=18): eighteen normal rats were injected intravenously with 0.2 ml culture media containing 10µM (0.01M) ATRA and 1 × 10^6 MSCs after one day of cisplatin injection, then each group was subdivided into 3 subgroups according to time of sacrificing, Day 3 subgroup (N=6): rats were scarificed after 3 days, Day 7 subgroup (N=6): rats were scarificed after 7 days, Day 11 subgroup (N=6): rats were scarificed after 11 days. Kidney function parameters, tissue oxidative stress markers, gene expression of Caspase-3, NF-kB,
TGβ1, IL6, HIF1α and VEGF were determined, histopathological studies on kidney tissues, immunohistochemistry for apoptotic marker Caspase-3 and immunofl- ourscence for vascular endothelial marker CD31 were determined.
Results: Biochemical markers (SCr, BUN and MAU), oxidative stress markers (MDA and NO), antioxidant markers (GSH and SOD) activity, apoptotic marker Caspase-3, inflammatory markers NFKB, TGFβ1, IL-6, angiogenic markers HIF1α, and VEGF showed no significant changes in the first three normal groups, while their levels significantly increased in cisplatin group. RA treated group and Msenchymal stem cells (MSCs) treated group showed statistically significant lower level of SCr, BUN, MAU, MDA and NO, apoptotic marker Caspase-3, inflammatory marker NFKB, TGFβ1, IL-6 and statistically significant higher levels of angiogenic markers HIF1α, and VEGF, while (RA + MSCs) showed the most decrease in their levels, and the most increase in the levels of angiogenic markers HIF1α and VEGF. With respect to histopathological studies there were no significant histopathological changes in the first three groups, while cisplatin group showed higher inner cortical and outer medullary degenerative score. In the three treated groups (RA group, MSCs group) showed higher cortical and medullary regenerative indices that reach its maximum it the combined group (RA+MSCs).
Conclusion: ADMSCs have renoprotective effects against acute kidney injury induced by cisplatin and may be used as an ideal cells for in vivo therapy of acute kidney injury, ATRA is an excellent inducer for ADMSCs against acute kidney injury induced by cisplatin, besides its role in the amelioration of Kidney function.