TNF-α mediates increased susceptibility to ischemic AKI in diabetes

Gao G, Zhang B, Ramesh G, Betterly D, Tadagavadi RK, Wang W, Reeves WB. TNF-alpha mediates increased susceptibility to ischemic AKI in diabetes. Am J Physiol Renal Physiol 304: F515-F521, 2013. First published January 2, 2013; doi:10.1152/ajprenal.00533.2012.-Diabetes is a risk factor for the development of acute kidney injury (AKI) in humans and rodents. However, the mechanistic basis for this observation is unknown. The present studies evaluated the role of inflammation and TNF-alpha in ischemic AKI in a model of type 2 diabetes mellitus (DM). Diabetic (db/db) and nondiabetic (db/+) littermates were subjected to 20 min of bilateral renal ischemia. The nondiabetic mice developed only mild and transient renal dysfunction. In contrast, the equivalent ischemic insult provoked severe and sustained renal dysfunction in the db/db mice. The expression of TNF-alpha and Toll-like receptor 4 (TLR4) mRNA was measured in the kidneys of diabetic mice before and after renal ischemia; db/db mice exhibited greater increases in TNF-alpha and TLR4 mRNA expression following ischemia than did db/+. In addition, urinary excretion of TNF-alpha after ischemia was higher in db/db mice than in db/+ mice. To determine the possible role of TNF-alpha in mediating the enhanced susceptibility of diabetic mice to ischemic injury, db/db mice were injected with either a neutralizing anti-mouse TNF-alpha antibody or nonimmune globulin and then subjected to 20 min of bilateral renal ischemia. Treatment of the db/db mice with the TNF-alpha antibody provided significant protection against the ischemic injury. These data support the view that diabetes increases the susceptibility to ischemia-induced renal dysfunction. This increased susceptibility derives from a heightened inflammatory response involving TNF-alpha and perhaps TLR4 signaling.