Abstract 18599: Diabetes Aggravates Both Acute Kidney Injury (AKI) After Acute Myocardial Infarction and AKI After Ischemia-Reperfusion by Distinct Mechanisms
Purpose: Diabetes (DM) increases the severity of acute kidney injury (AKI), in which roles of caspase-mediated apoptosis and RIP1/RIP3-dependent necroptosis have been implicated. Here, we examined whether distinct cell death mechanisms are involved in two types of AKI, myocardial infarction (MI)-triggered cardio-renal syndrome (CRS) and renal ischemia/reperfusion (I/R).
Methods and Results: We used OLETF, a rat model of type 2 DM at 25-30 weeks old, when early nephropathy is indicated by increased urinary protein without increase in serum creatinine (sCr), and its non-DM control, LETO. In the first series of experiments, to prepare a model of CRS, MI was induced by ligation of a left coronary artery for 12 hrs. Though sCr level was not increased in either OLETF or LETO after MI, immunostaining revealed that the area positive for kidney injury molecule-1, a marker of AKI, was significantly increased by 5.3 fold (P<0.05) only in OLETF. The mRNA levels of toll-like receptor (TLR) 2, TLR4 and TNFα in the kidney were increased by 1.6, 1.2, 1.5 fold, respectively, in OLETF but not in LETO. Immunoblotting showed that levels of phospho-p38MAPK and phospho-JNK, downstream kinases of TLRs, were significantly elevated in OLETF. Cleavage of caspase 3, which promotes apoptosis, and cleavage of RIP1, which suppresses necroptosis, in the kidney after MI were increased more in OLETF than in LETO. In the second series of experiments, to induce AKI by I/R, rats were subjected to unilateral nephrectomy and then 30-min renal artery occlusion/24-hr reperfusion in the contralateral kidney. After renal I/R, elevation of sCr was greater in OLETF than in LETO (sCr: 1.9±0.4 vs. 3.8±0.3 mg/dl, P<0.05). Cleaved caspase 3 levels in the kidney were comparable in OLETF and LETO. RIP1 and RIP3 levels were similar in the two groups at baseline, but I/R significantly upregulated RIP3 protein level by 3.7 fold only in OLETF.
Conclusions: Apoptosis, but not necroptosis, via the TLR/TNF pathway, is involved in AKI induced by CRS in OLETF. In contrast, necroptosis, but not apoptosis, plays a major role in aggravation of I/R-induced AKI in OLETF. Two distinct cell death mechanisms play roles in DM-induced aggravation of AKI, depending on the type and/or strength of insult to cause AKI.
Author Disclosures: K. Ohno: None. A. Kuno: None. S. Muratsubaki: None. W. Ohwada: None. K. Nakata: None. T. Yano: None. M. Tanno: None. T. Miki: None. T. Miura: None.
- © 2016 by American Heart Association, Inc.