Different sulfonylureas induce the apoptosis of proximal tubular epithelial cell differently via closing KATP channel

Abstract

BackgroundSulfonylureas (SUs) are widely prescribed for the treatment of type 2 diabetes (T2DM). Sulfonylurea receptors (SURs) are their main functional receptors. These receptors are also found in kidney, especially the tubular cells. However, the effects of SUs on renal proximal tubular epithelial cells (PTECs) were unclear.MethodsThree commonly used SUs were included in this study to investigate if different SUs have different effects on the apoptosis of PTECs. HK-2 cells were exposed to SUs for 24 h prior to exposure to 30 mM glucose, the apoptosis rate was evaluated by Annexin/PI flow cytometry. Bcl-2, Bax and the ratio of LC3II to LC3I were also studied by western blot in vitro. Diazoxide was used to evaluate the role of KATP channel in SUs-induced apoptosis of PTECs. A Student’s t-test was used to assess significance for data within two groups.ResultsTreatment with glibenclamide aggravated the apoptosis of HK-2 cells in high-glucose, as indicated by a significant decrease in the expression of Bcl-2 and increase in Bax. Additionally, the decreased LC3II/LC3I reflects that the autophagy was inhibited by glibenclamide. Similar but less pronounced change was found in glimepiride group, however, nearly opposite effects were found in gliclazide group. Further, the effects of glibenclamide on apoptosis promotion and the decreased LC3II/LC3I were ameliorated obviously by treatment with 100uM diazoxide. The potential protection effect of gliclazide was also inhibited after opening the KATP channel.ConclusionOur results suggest that, the effects of glibenclamide and glimepiride on PTECs apoptosis, especially the former, were achieved in part by closing the KATP channel. In contrast to glibenclamide and glimepiride, therapeutic concentrations of gliclazide showed an inhibitory effect on apoptosis of PTECs, which may have a benefit in the preservation of functional PTECs mass.

Effects of Sulfonylureas Treatment on Apoptosis, Total Superoxide Dismutase activity and Some Biochemical Parameters in Type 2 Diabetic Patients

“…Recently it was shown that death receptors can be established in a soluble form in the bloodstream (24). Levels of serum (TNF-R1) concentration (pg/mL) for studied groups showed that there were not significant differences between patients group when compared with control group , so the result of the current study showed that using of Sulfonylureas therapy may reduce TNF-R1 concentration .This finding was consistent with literature data which know that the levels of serum TNF and its receptors were significantly decreased in diabetic patients with Sulfonylureas treatment (25). The results of TRAIL-R2 concentration (pg/mL) showed elevated significant difference between patients groups (P<0.0001), when compared to control groups.…”

A High-Content Screen for the Identification of Plant Extracts with Insulin Secretion-Modulating Activity

“…Different types of sulfonylureas are widely used to treat type 2 diabetes mellitus (T2DM) [ 24 , 25 ]. Hence, we tested the effects of tolbutamide, chlorpropamide, glipizide, glibenclamide and glimepiride, all of which are sulfonylureas, for their abilities to stimulate insulin secretion.…”

Role of renal tubular programed cell death in diabetic kidney disease

“…Zhang et al 71 . reported that different sulfonylurea compounds could mediate PTEC apoptosis by closing the K ATP channel at different binding selectivity and reversibility.…”

“…69 Additionally, Mou et al revealed that the apoptosis of tubules was significantly decreased by a combination of prostaglandin E1 and angiotensin-converting enzyme (ACE) inhibitors, which showcased the remarkable protective effect prostaglandin E1 and ACE inhibitors have on renal function in DKD. 70 Zhang et al 71 reported that different sulfonylurea compounds could mediate PTEC apoptosis by closing the K ATP channel at different binding selectivity and reversibility. A therapeutic effect of gliclazide on the inhibition of PTEC apoptosis was also observed, which benefited the preservation of functional PTEC mass.…”