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SummaryActivation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCα and PKCβ by TPA (12-OTetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCβ but not PKCα activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCβ by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCβ2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCβ signaling, which leads to MR stabilization and its transcriptional activities.( 3) which have elucidated that add-on therapy of MR antagonist is beneficial for the improvement of prognosis in heart failure patients, we became aware in recent decades that aberrant MR activation could be crucially involved in cardiovascular morbidity and mortality. Indeed it is prevalently known that primary aldosteronism, in which aldosterone excess causes hypertension through MR activation, increases the risk of cardiovascular events such as myocardial infarction and arrhythmia by three-to five-fold over essential hypertension.4) Additionally, add-on treatment of an MR antagonist has also been demonstrated to be effective in resistant hypertension (RHTN), 5) suggesting that activation of MR would play a key role on the progression of RHTN. These clinical findings has been driving many researchers to focus on the molecular mechanism of aberrant MR activation in RHTN and its related organ damages, but a detailed mechanism remains largely unknown.Hypertension is approximately twice as frequent in diabetes mellitus (DM) compared with non-DM patients 6) and RHTN is highly associated with DM, 7) but the etiology of hypertension and cardiovascular complications in DM patients is not fully understood.8) It was reported that add-on treatment of an MR antagonist alleviated persistent albuminuria in DM patients with conventional antihypertensive treatment, 9) which suggests that aberrant MR activation could be also an underlying mechanism of hypertension in DM patients. We have recently proposed such MR antagonist-responsive hypertension as "MR-associated hypertension" 10) and investigated the molecular actions of MR, among which we identified several novel coregulators of MR. 11,12) DM is a major cause of macro-and microvascular complications. The molecular mechanisms for those vascular complications have been explained by several moFrom the

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