Combined Systemic Intake of K-ATP Opener (Nicorandil) and Mesenchymal Stem Cells Preconditioned With Nicorandil Alleviates Pancreatic Insufficiency in a Model of Bilateral Renal Ischemia/Reperfusion Injury

Abstract

We used nicorandil, a K-ATP channel opener, to study the role of these channels in the amelioration of renal ischemia/reperfusion (I/R)-induced pancreatic injury, and the possible involvement of PI3K/Akt/mTOR signaling pathway. Forty-two male Wistar rats were included in this study, six were sacrificed for extraction of bone marrow mesenchymal stem cells (BM-MSCs) and conducting the in-vitro work, the others were included in vivo study and equally divided into six groups. Group 1 (sham control), but groups 2–6 were subjected to bilateral renal I/R: Group 2 (I/R); Group 3 (I/R-NC), treated with nicorandil; Group 4 (I/R-MSCs), treated with BM-MSCs; Group 5 (I/R-MSCC), treated with nicorandil-preconditioned BM-MSCs; Group 6 (I/R-NC-MSCC), treated with both systemic nicorandil and preconditioned BM-MSCC. Renal injury and subsequent pancreatic damage were detected in the I/R group by a significant increase in serum urea, creatinine, fasting glucose, and pancreatic enzymes. The pancreatic tissues showed a reduction in cellularity and a significant decrease in the expression of the cell survival pathway, PI3K/Akt/mTOR, in the I/R group compared to the control. Preconditioning MSCs with nicorandil significantly enhanced the proliferation assay and decreased their apoptotic markers. Indeed, combined systemic nicorandil and nicorandil-preconditioning maintained survival of MSC in the pancreatic tissue and amelioration of apoptotic markers and pancreatic TNF-α production. Histologically, all treated groups revealed better pancreatic architecture, and increased area % of anti-insulin antibody and CD31, which were all best observed in the NC-MSCC group. Thus, using K-ATP channel opener was efficient to enhance PI3K/Akt/mTOR expression levels (in vivo and in vitro).

Comparison of the protective effects of insulin and saponin on renal ischemia-reperfusion injury

“…We reported a significant increase concerning the levels of serum glucose in the IR group, indicating that an impaired pancreatic structure was occurred after IR (16). It has been proposed that hyperglycemia induces oxidative stress and decreases endogenous antioxidant enzymes through different mechanisms.…”

Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway

“… 18 , 40 In contrast, we reported that pretreatment of MSC with cardioprotective drug is a clinically promising method to enhance the effect of MSC and exosomes on cardiac repair for AMI. 18 , 26 , 27 Since Nicorandil has been proven to have significant effects in protecting cardiac cells, reducing cardiovascular events and directly protecting MSC from apoptosis under H/SD conditions in vitro, 25 , 31 , 32 we used nicorandil as pretreatment drug for MSC in the present study and found that intramyocardial injection of MSC NIC -exo had superior therapeutic effects in cardiac repair post-MI with cardiac function enhanced, infarct size and collagen area minimized, inflammatory cells and cytokines infiltration suppressed, angiogenesispromoted, as well as macrophage M2 polarization facilitated in the infarct region.…”

“…24,25 Our previous studies found that both treatment with cardioprotective drugs (atorvastatin and Tongxinluo) and the two drug-pretreated MSC could enhance the effects of cardiac repair post-AMI via altering the mRNA or non-coding RNA profiles of their exosomes. 18,26,27 Similar to statins and Tongxinluo, the nicorandil treatment also showed superior cardioprotective effect to MSC alone in heart failure rats [28][29][30][31] and nicorandil-pretreatment could protect MSC from hypoxia/serum-deprivation injury in vitro as well. 31,32 Therefore, we hypothesized that nicorandilpretreated MSC-derived exosomes (MSC NIC -exo) could have distinct non-coding RNA profiles and also better therapeutic effects than MSC-derived exosomes (MSC-exo) in treating AMI.…”

“… 18 , 26 , 27 Similar to statins and Tongxinluo, the nicorandil treatment also showed superior cardioprotective effect to MSC alone in heart failure rats 28–31 and nicorandil-pretreatment could protect MSC from hypoxia/serum-deprivation injury in vitro as well. 31 , 32 Therefore, we hypothesized that nicorandil-pretreated MSC-derived exosomes (MSC NIC -exo) could have distinct non-coding RNA profiles and also bettertherapeutic effects than MSC-derived exosomes (MSC-exo) in treating AMI.…”