All-trans Retinoic Acid Reduces Renal Ischemia-Reperfusion Injury By Anti-Inflammation And Anti-Fibrosis

Acute kidney injury(AKI)is a group of clinical syndromes characterized by acute renal insufficiency.Characteristics of AKI are high incidence and poor prognosis.Ischemia-reperfusion injury(IRI)is one of the most frequent causes of AKI caused by shock,sepsis,and kidney transplantation surgery.Therefore,it is necessary and urgent to study the drugs that can cure AKI and study the mechanism.In recent years,various drugs have been proven to have therapeutic effects on AKI,including western medicine,Chinese medicine,hormones,cytokines,and growth factors.Retinoic acid is divided into all-trans retinoic acid(at RA)and 9-cis-RA.Retinoids can not only treat cancers,but also have therapeutic effects on various kidney diseases.Retinoic acid could improve renal function by reducing urinary protein,glomerular and tubular damage in rats with acute or chronic mesangial proliferative glomerulonephritis and puromycin nephropathy.We find that the expression of pro-inflammatory cytokines of i NOS and IL-1β is up-regulated and the anti-inflammatory cytokines IL-10 is down-regulated one day after renal ischemia-reperfusion injury in vivo.A concentration of at RA at 10 mg/kg for 3 days could reduce i NOS,IL-1β,and IL-10,while low concentration or low pretreatment time does not.At RA can also reduce renal fibrosis after renal ischemia-reperfusion with longer treatment time and the higher the treatment concentration.We find that IL-10 is decreased when the human renal tubular epithelial cells HK2 cell is treated after hypoxia-reoxygenation.At RA could upregulate the expression of IL-10 in HK2 cell with a concentration at 10 μM.After hypoxia and reoxygenation,markers of fiborosi and epithelial mesenchymal transition ar up-regulated,while E-cadherin is downregulated.These trends have been reversed after at RA pretreatment.These results confirm that at RA could reduce inflammation and fibrosis in renal tubular epithelial cells.We review high-throughput microarray data to screen out differentially expressed m RNA in the renal cortex after at RA treatment.We concluded that IDH1,a protein involved in oxidative metabolism is down-regulated after at RA addition.We consider the proteins which could regulate cell cycle and find that many proteins are down-regulated after prolonged and high concentrations of at RA,suggesting that at RA can reduce cell proliferation by inducing cell cycle arrest.The upstream and midstream proteins of the Wnt-β-catenin pathway are inhibited after at RA treatment.In conclusion,at RA can decrease renal ischemia-reperfusion injury,inflammation,and fibrosis.