Background: Type 1 cardiorenal syndrome (CRS) is defined as acute kidney injury caused by acute cardiac dysfunction, and type 2 diabetes mellitus (T2DM) is an independent risk factor for renal susceptibility to CRS. Recently, EMPA-REG OUTCOME demonstrated that an SGLT-2 inhibitor improves renal outcomes in patients with T2DM at high risk for cardiovascular events, but its mechanism remains unclear. Here, we examined whether activation of renal toll-like receptors (TLRs) is involved in worsening of CRS by T2DM and whether such an effect of T2DM, if any, can be attenuated by an SGLT-2 inhibitor.
Methods and Results: Myocardial infarction (MI) was induced by coronary ligation in OLETF, a rat model of T2DM, and LETO, non-diabetic controls, at 25-30 weeks of age. Sham-operated rats served as non-MI controls. Body weight (617±23 vs. 537±13 g) and glycoalbumin level (16.1±1.7 vs. 10.6±0.3%) were higher in OLETF than in LETO. Kidney samples taken at 12 hrs after the operation were analyzed. Renal mRNA levels of kidney injury molecule-1 (KIM-1), TLR2 and myeloid differentiation factor 88 (MyD88), an adaptor protein for TLRs, were significantly higher in sham-operated OLETF than in LETO. Induction of MI further increased renal mRNA levels of TLR2, TLR4, MyD88 and proinflammatory cytokines (IL-6, TNF-α and TGF-β) in OLETF, but such changes were not observed in LETO. Phospho-p38MAPK and nuclear NF-κB-p65 were increased by MI only in OLETF, indicating TLR activation. MI also increased the KIM-1-positive area by 5.3 fold in OLETF but not in LETO. Pretreatment of OLETF with Cu-CPT22 (3 mg/kg), a TLR1/2 blocker, before MI reduced mRNA levels of KIM-1, TLR2, TLR4 and MyD88 and the KIM-1-positive area compared with those in vehicle-treated OLETF. Treatment with canagliflozin (1 mg/kg/day), an SGLT-2 inhibitor, for 14 days significantly reduced glycoalbumin level (12.9±0.4%) and renal mRNA levels of TLR2, TLR4 and MyD88 by 28%, 47% and 36%, respectively, in OLETF.
Conclusion: Increased susceptibility to CRS in T2DM is mediated by augmented activation of TLRs and subsequent NF-κB-mediated inflammatory signaling in the kidney. Canagliflozin suppresses T2DM-induced upregulation of TLRs in the kidney, potentially normalizing renal susceptibility to CRS.