Intracellular Renin Inhibits Mitochondrial Permeability Transition Pore via an Activated Mitochondrial ERK1/2 during Ischemia in Diabetic Hearts

Purpose: Diabetes mellitus (DM) is one of most critical risks of heart failure. Although the ischemic resistance in DM hearts have been reported, the precise mechanism remains elusive and involvement of intracellular renin has not been studied. Methods & Results: (1) When isolated hearts from Wistar rats (non-DM) and Goto-Kakizaki rats (DM) were subjected to ischemia for 70 min, DM hearts exhibited higher LV developed pressure (113 ± 3 mmHg vs. 90 ± 7 mmHg of non-DM, P < .05) and lower LV end-diastolic pressure (10.3 ± 0.7 mmHg vs. 15.9 ± 0.8 mmHg of non-DM, P < .05) than those of non-DM hearts, indicating the ischemic resistance in DM hearts. (2) The ischemic resistance in DM hearts was abolished by aliskiren (a direct renin inhibitor) or U0126 (an ERK1/2 inhibitor). (3) DM hearts exhibited the increased intracellular renin and activated mitochondrial ERK1/2. (4) In DM hearts, renin hyperpolarized mitochondrial membrane potential (JC-1; 2.81 ± 0.01 of renin, vs. 2.63 ± 0.01 of control, P < .05) in an U0126-sensitive manner (2.64 ± 0.02 of renin + U0126, vs. renin, P < .05). (5) Renin attenuated the atractyloside (Atr, an mPTP opener)-induced membrane potential depolarization (JC-1; 2.09 ± 0.01 of Atr, vs. 2.25 ± 0.02 of Atr + renin, P < .05) in an U0126-sensitive manner (2.10 ± 0.01 of Atr + renin + U0126, vs. Atr + renin, P < .05) in DM hearts. Conclusions: Intracellular renin may inhibit mPTP opening during ischemia through the activated mitochondrial ERK1/2, which may result in the ischemic resistance in DM hearts.