Protection Of Curcumin Against Renal Injury In An Insulin Resistance Modelof Rats

OBJECTIVE:To investigate the protection of curcumin against renal injury in an insulin resistancemodel of rats induced by high fructose.METHODS:Male Sprague-Dawley rats were randomly divided into five groups: controlgroup receiving water,10%wt/vol fructose (in drinking water)-fed groupsreceiving water,30mg/kg curcumin,60mg/kg curcumin, and10mg/kg pioglitazone, respectively. After4weeks of fructose feeding, curcuminand pioglitazonewere orally administered daily at10:00-11:00AM for next4weeks. Body weight was measured weekly. At the end of drug treatment, OGTT (oral glucose tolerance test) was performed. Serum TG (triglyceride), TC(total Cholesterol), LDL-C(low density lipid cholesterol), HDL-C(high density lipid cholesterol), VLDL-C(very low density lipid cholesterol) and renal H202were measured. Rat kidney tissues were stained with oil-red O reagent and hematoxylin-eosin (HE). The key proteins in insulin signaling and NLRP3(NACHT, LRR and PYD domains-containing protein3) inflammasome were detected by Western blotting.RESULTS:1. Effects of curcumin on dyslipidemia, renal insulin resistance, and oxidative stress:Compared to control group, the body weight in fructose-fed rats was increased significantly, and impaired glucose tolerance was observed in fructose-fed rats. The levels of serum TG, TC, LDL-C, HDL-C, VLDL-C and renal H2O2were als increased in fructose-fed rats. Curcumin significantly decreased body weight, and reversed the impaired glucose tolerance in this model. Curcumin also significantly reversed dyslipidemia by reduction of serum TG, TC LDL-C, HDL-C, and VLDL-C in fructose-fed rats.Curcumin at dose60mg/kg, but not30mg/kg, decreased of renal H2O2levels in this animal model.2. Effects of curcumin on renal pathologic changes in fructose-fed rats:Oil-red staining analysis and HE staining analysis indicated that renal injury was occurred and lipids were deposited in renal tubular epithelial cells in fructose-fed rats, which were restored by the treatment of curcumin.3. Effects of curcumin on renal insulin signaling pathway in fructose-fed rats:There was significant difference in Serine phosphorylation levels of IRS1(insulin receptor substrate1) as a result of high fructose consumption in rats compared with control group. Furthermore, phosphorylation levels of PI3K (phosphatidylinositol-3-kinase) and Akt(protein kinase B) was decreased in fructose-fed rats. However, there were no significant differences in phosphorylation levels of IRS1(Tyr) between control and fructose-fed groups. Curcumin at60mg/kg increased P-IRS1(Tyr), P-PI3K, and P-Akt protein levels and decreased protein levels of P-IRS1(Ser) in the kidney of fructose-fed rats. Curcumin at30mg/kg increased renal protein levels of P-IRS1(Tyr), but failed to alter P-PI3K, P-Akt and P-IRS1(Ser) in this animal model.4. Effects of curcumin on renal NLRP3inflammasome activation in fructose-fed rats: Fructose significantly increased protein levels of renal NLRP3, pro-Caspase-1(pro-form of cysteine-dependentaspartate-directed proteases), Caspase-1(cysteine-dependentaspartate-directed proteases), and IL-1β (interleukin1β) in rats cpmpared with control group, but there was no significant difference in pro-IL-1β (pro-form of interleukin1β) between control group and fructose-fed group. Curcumin was shown to significantly decrease renal protein levels of the NLRP3, Caspase-1, but failed to affect renal pro-Caspase-1and pro-IL-1β in this animal model.CONCLUSION:Curcumin was confirmed to improve insulin sensitivity, reverse dyslipidaemia in fructose-fed rats. The ability of curcumin to restore renal insulin resistance may depend on its anti-inflammatory activity, resulting in the decreased levels of renal NLRP3and mature of cytokine IL-1β in fructose-fed animals.Curcumin may also regulate renal insulin signaling pathway in fructose-fed rats possibly by its anti-oxidation. These results may lay the foundation for curcumin to prevent and treat renal injury induced by high fructose.