Metformin regulates atrial SK2 and SK3 expression through inhibiting the PKC/ERK signaling pathway in type 2 diabetic rats

Abstract

BackgroundOur previous study showed that metformin regulates the mRNA and protein levels of type 2 small conductance calcium-activated potassium channel (SK2) and type 3 small conductance calcium-activated potassium channels (SK3) in atrial tissue as well as the ion current of atrial myocytes in rats with type 2 diabetes mellitus (T2DM), but the underlying signaling mechanism is unknown. This study aimed to investigate whether metformin regulates atrial SK2 and SK3 protein expression in T2DM rats though the protein kinase C (PKC)/extracellular signal-regulated kinase (ERK) signaling pathway.MethodsA T2DM rat model was established using a high-fat and high-sugar diet combined with a low-dose intraperitoneal injection of streptozotocin (STZ). The rats were randomly divided into the following five groups: the control group, the untreated T2DM group, the metformin-treated only group, the phorbol 12-myristate 13-acetate (PMA; a PKC agonist administered by intraperitoneal injection) treatment group, and the recombinant human epidermal growth factor (rh-EGF; an ERK agonist administered by tail vein injection) treatment group. The activity of PKC in atrial tissues was assayed by a PKC kinase activity assay kit. The protein expression of SK2, SK3, and phosphorylated ERK (pERK) were determined by western blotting and immunohistochemistry.ResultsCompared with the Control group, atrial PKC activity and pERK and SK3 protein expression were increased, while SK2 protein expression was decreased in atrial tissues of T2DM rats. Eight weeks of metformin treatment inhibited the PKC activity and pERK and SK3 expression, and elevated SK2 expression compared with the T2DM group. Compared with the metformin-treated only group, the injection of rh-EGF increased pERK and SK3 expression, and decreased SK2 expression; the injection of PMA increased PKC activity and SK3 expression, and decreased SK2 expression. In addition, the injection with PMA significantly elevated the expression of pERK.ConclusionsThe PKC/ERK signaling pathway is involved in the downregulation of SK2 expression and the upregulation of SK3 expression in the atrium of T2DM rats. Long-term metformin treatment prevents the SK2 downregulation and the SK3 upregulation through inhibiting the PKC/ERK signaling pathway.Electronic supplementary materialThe online version of this article (10.1186/s12872-018-0950-x) contains supplementary material, which is available to authorized users.

Urinary Bladder Weight and Function in a Rat Model of Mild Hyperglycemia and Its Treatment With Dapagliflozin

“…Although glucose level remained stable at that level in batch 1, they declined over time in batch 2, reaching pre-dapagliflozin and end-of-study levels of about 200 mg/dl. Although the end-of-study glucose level in batch 1 was in line with reports of others in this model (Zhang et al, 2012; Lee et al, 2018; Li et al, 2018; Liu et al, 2018), those of batch 2 were not and probably cannot be considered diabetic but rather as mildly hyperglycemic. We consider a partial recovery of pancreatic beta cells after a less effective destruction by STZ (Desgraz et al, 2011; Cheng et al, 2016) as the most likely explanation for the decline of blood glucose in batch 2.…”

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“…These findings indicated that the effects of lidocaine on CFA-induced rats were significantly reversed by rh-EGF. Since rh-EGF is an ERK agonist ( 43 ), data from the present study suggest that rh-EGF + lidocaine significantly reduced TWL, MWT and frequency responses to cold stimulation but significantly increased TNF-α, IL-1β and IL-6 levels through activating the ERK pathway.…”

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