Diabetes increases the susceptibility to acute kidney injury after myocardial infarction through augmented activation of renal Toll-like receptors in rats

Am J Physiol Heart Circ Physiol. 2017 Dec 1;313(6):H1130-H1142. doi: 10.1152/ajpheart.00205.2017. Epub 2017 Aug 19.


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 the roles of renal Toll-like receptors (TLRs) in the impact of DM on AKI after MI. MI was induced by coronary artery ligation in Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a rat DM model, and Long-Evans-Tokushima-Otsuka (LETO) rats, nondiabetic controls. Sham-operated rats served as no-MI controls. Renal mRNA levels of TLR2 and myeloid differentiation factor 88 (MyD88) were significantly higher in sham-operated OLETF rats than in sham-operated LETO rats, although levels of TLR1, TLR3, and TLR4 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- and 4.0-fold, respectively, and their mRNA levels were increased in OLETF but not LETO rats. The increased KIM-1 and NGAL expression levels after MI in the OLETF kidney were associated with upregulated expression of TLR1, TLR2, TLR4, MyD88, IL-6, TNF-α, chemokine (C-C motif) ligand 2, and transforming growth factor-β1 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 chemokine (C-C motif) ligand 2 levels and activation of NF-κB, whereas NGAL levels and IL-6 and TNF-α expression levels were unchanged. The results suggest that DM increases the susceptibility to AKI after acute MI by augmented activation of renal TLRs and that TLR1/TLR2-mediated signaling mediates KIM-1 upregulation after MI.NEW & NOTEWORTHY This is the first report to demonstrate the involvement of Toll-like recpetors (TLRs) in diabetes-induced susceptibility to acute kidney injury after acute myocardial infarction. We propose that the TLR1/TLR2 heterodimer may be a new therapeutic target for the prevention of acute kidney injury in diabetic patients.

Keywords: Toll-like receptor; acute kidney injury; cardiorenal syndrome; diabetes; myocardial infarction.

MeSH terms

  • Acute Kidney Injury / etiology*
  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Acute-Phase Proteins / metabolism
  • Animals
  • Cell Adhesion Molecules / metabolism
  • Chemokine CCL2 / metabolism
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Disease Models, Animal
  • Kidney / metabolism*
  • Kidney / pathology
  • Lipocalin-2
  • Lipocalins / metabolism
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Myeloid Differentiation Factor 88 / metabolism
  • Myocardial Infarction / complications*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Rats, Inbred OLETF
  • Rats, Long-Evans
  • Signal Transduction
  • Toll-Like Receptor 1 / genetics
  • Toll-Like Receptor 1 / metabolism*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • Up-Regulation


  • Acute-Phase Proteins
  • Ccl2 protein, rat
  • Cell Adhesion Molecules
  • Chemokine CCL2
  • Havcr1protein, rat
  • Lcn2 protein, rat
  • Lipocalin-2
  • Lipocalins
  • Myd88 protein, rat
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Tlr2 protein, rat
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Mitogen-Activated Protein Kinases