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

Abstract

We previously reported that induced type 1 diabetes mellitus (DM) increases the susceptibility of acute kidney injury inducedby ischemia-reperfusion injury (IRI) in cynomolgus monkeys. In this follow-up study, we compared the expression ofselected markers in the renal tissues of monkeys subjected to bilateral renal IRI with and without diabetes. All tissues wereobtained from the original study. Renal biopsies were obtained before and 24 and 48 h after ischemia and were examinedfor 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 muscleactin, α-SMA), and cleaved caspase 3 (apoptosis). Generally, the expression of these markers differed in monkeys with andwithout DM. As compared with non-DM monkeys, DM monkeys had more cells that expressed KI-67 during progressionof acute kidney injury (AKI). Na+/K+ ATPase expression was clearly present at baseline in the basolateral tubular areas onlyin the non-DM monkeys. At 48 h, its expression in the basolateral area was not visible in DM monkeys, but was still presentin intercellular junctions of non-DM monkeys. The expression of TNF-α was 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 morecollapsed vessels were found at in DM at 24 h. At 48 h, the number of capillaries was less in DM compared with those fromnon-DM animals. DM monkeys had more interstitial CD3-positive cells than did non-DM monkeys at 24 and 48 h afterischemia. Finally, FSP-1-stained cells were more abundant in DM than non-DM at 24 and 48 h. Our results show that DMaggravates the recovery of renal ischemia/reperfusion injury by affecting tubular proliferation, capillary density, T cell infiltrationand by altering protein and mRNA expression of various genes involved in ion channel, inflammation, and fibroticchange. The results from this observational study demonstrate that DM aggravates the recovery of renal ischemia/reperfusioninjury by affecting multiple events including tubular necrosis, proliferation, function, inflammation and by inducingcapillary rarefaction in cynomolgus monkeys.