Downregulation of IL-1ß/p38 mitogen activated protein kinase pathway by diacerein protects against kidney ischemia/reperfusion injury in rats.

ABSTRACT

Renal ischemia-reperfusion (I/R) can be precipitated by multiple clinical situations that lead to impaired renal function and associated mortality. The resulting tubular cell damage is the outcome of complex disorders including, an inflammatory process with an overproduction of cytokines. Here, diacerein (DIA), an inhibitor of proinflammatory cytokine interleukin-1 beta (IL-1ß), was investigated against renal I/R in rats. DIA was orally administrated (50 mg/kg/day) for ten days before bilateral ischemia for 45 min with subsequent 2 hr. reperfusion. Interestingly, DIA alleviated the renal dysfunction and histopathological damage in the renal tissues. Pretreatment with DIA corrected the oxidative imbalance by prevented reduction in antioxidant levels of GSH and SOD, while it decreased the elevation of the oxidative marker, MDA. In addition, DIA downregulated IL-1ß and TNF-α expression in the renal tissues. Consequent to inhibition of the oxidative stress and inflammatory cascades, DIA inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Therefore, downstream targets for p38 MAPK were also inhibited via DIA which prevented further increases of inflammatory cytokines and the apoptotic marker, caspase-3. Collectively, this study revealed the renoprotective role of DIA for renal I/R and highlighted the role of p38 MAPK encountered in its therapeutic application in renal disease.