Acute kidney injury (AKI) after acute myocardial infarction (MI) worsens the prognosis of MI patients. Although type 2 diabetes mellitus (DM) is a major risk factor of AKI after MI, the underlying mechanism remains unclear. Here, we examined roles of renal toll-like receptors (TLRs) in the impact of DM on AKI after MI. MI was induced by coronary artery ligation in OLETF, a rat DM model, and LETO, non-diabetic controls. Sham-operated rats served as no-MI controls. Renal mRNA levels of TLR2 and MyD88 were significantly higher in sham-operated OLETF than in sham-operated LETO, though levels of TLR1, TLR3, and TRL4 were similar. At 12 h after MI, protein levels of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the kidney were elevated by 5.3 fold and 4.0 fold, respectively, and their mRNA levels were increased in OLETF but not in LETO. The increased KIM-1 and NGAL expression levels after MI in the OLETF kidney were associated with up-regulated expression of TLR1, TLR2, TLR4, MyD88, IL-6, TNF-α, CCL2 and TGF-β and also with activation of p38 MAPK, JNK, and NF-κB. Cu-CPT22, a TLR1/TLR2 antagonist, administered before MI significantly suppressed MI-induced upregulation of KIM-1, TLR2, TLR4, MyD88 and CCL2 levels and activation of NF-κB, whereas NAGL level and IL-6 and TNF-α expression levels were unchanged. The results suggest that DM increases susceptibility to AKI after acute MI by augmented activation of renal TLRs and that TLR1/TLR2-mediated signaling mediates KIM-1 upregulation after MI.

作者：Kouhei, Ohno；Atsushi, Kuno；Hiromichi, Murase；Shingo, Muratsubaki；Takayuki, Miki；Masaya, Tanno；Toshiyuki, Yano；Satoko, Ishikawa；Tomohisa, Yamashita；Tetsuji, Miura

来源：American journal of physiology. Heart and circulatory physiology 2017 年