Evaluation of Selected Markers in Kidneys of Cynomolgus Monkey (Macaca fascicularis) with Induced Diabetes during Renal Ischemia-reperfusion Injury.

We previously reported that induced type 1 diabetes mellitus (DM) increases the susceptibility of acute kidney injury in- duced by ischemia-reperfusion injury (IRI) in cynomolgus monkeys. In this follow-up study, we compared the expression of selected markers in the renal tissues of monkeys subjected to bilateral renal IRI with and without diabetes. All tissues were obtained from the original study. Renal biopsies were obtained before and 24 and 48 h after ischemia and were examined for expression of KI-67 (tubular proliferation), Na+ /K+ ATPase (sodium-potassium pump), TNF-α(tumor necrosis factor-α, inflammation), CD31 (microvessels), CD3 (T-cells), 2 fibrotic markers (fibroblast specific protein-1, FSP-1;α-smooth muscle actin,α -SMA), and cleaved caspase 3 (apoptosis). Generally, the expression of these markers differed in monkeys with and without DM. As compared with non-DM monkeys, DM monkeys had more cells that expressed KI-67 during progression of acute kidney injury (AKI). Na+ /K+ ATPase expression was clearly present at baseline in the basolateral tubular areas only in the non-DM monkeys. At 48 h, its expression in the basolateral area was not visible in DM monkeys, but was still present in intercellular junctions of non-DM monkeys. The expression of TNF-αwas higher in DM before and 48 h after ischemia. Before and 24 h after ischemia, the number of CD31-positive capillaries was not different between 2 groups, although more collapsed vessels were found at in DM at 24 h. At 48 h, the number of capillaries was less in DM compared with those from non-DM animals. DM monkeys had more interstitial CD3-positive cells than did non-DM monkeys at 24 and 48 h after ischemia. Finally, FSP-1-stained cells were more abundant in DM than non-DM at 24 and 48 h. Our results show that DM aggravates the recovery of renal ischemia/reperfusion injury by affecting tubular proliferation, capillary density, T cell infil- tration and by altering protein and mRNA expression of various genes involved in ion channel, inflammation, and fibrotic change. The results from this observational study demonstrate that DM aggravates the recovery of renal ischemia/reperfusion injury by affecting multiple events including tubular necrosis, proliferation, function, inflammation and by inducing capillary rarefaction in cynomolgus monkeys.

Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states.

Berberine has been shown to have antidiabetic properties, although its mode of action is not known. Here, we have investigated the metabolic effects of berberine in two animal models of insulin resistance and in insulin-responsive cell lines. Berberine reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice. Similarly, berberine reduced body weight and plasma triglycerides and improved insulin action in high-fat-fed Wistar rats. Berberine downregulated the expression of genes involved in lipogenesis and upregulated those involved in energy expenditure in adipose tissue and muscle. Berberine treatment resulted in increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and L6 myotubes, increased GLUT4 translocation in L6 cells in a phosphatidylinositol 3' kinase-independent manner, and reduced lipid accumulation in 3T3-L1 adipocytes. These findings suggest that berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity.