Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes

Abstract

Diabetes-induced podocyte apoptosis is considered to play a critical role in the pathogenesis of diabetic kidney disease (DKD). We proposed that hyperglycaemia can induce podocyte apoptosis by inhibiting the action of podocyte survival factors, thus inactivating the cellular effects of insulin signalling. In this study, we aimed to determine the effects of linagliptin on high glucose-induced podocyte apoptosis. Linagliptin reduced the increase in DNA fragmentation as well as the increase in TUNEL-positive cells in podocytes induced by high-glucose condition. Furthermore, linagliptin improved insulin-induced phosphorylation of insulin receptor substrate 1 (IRS1) and Akt, which was inhibited in high-glucose conditions. Adenoviral vector-mediated IRS1 overexpression in podocytes partially normalised DNA fragmentation in high-glucose conditions, while downregulation of IRS1 expression using small interfering RNA increased DNA fragmentation even in low-glucose conditions. Because reactive oxygen species inhibit glomerular insulin signalling in diabetes and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important intrinsic antioxidative systems, we evaluated whether linagliptin increased Nrf2 in podocytes. Highglucose condition and linagliptin addition increased Nrf2 levels compared to low-glucose conditions. In summary, linagliptin offers protection against DKD by enhancing IRS1/Akt insulin signalling in podocytes and partially via the Keap1/Nrf2 pathway. Our findings suggest that linagliptin may induce protective effects in patients with DKD, and increasing IRS1 levels could be a potential therapeutic target in DKD.Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease and end-stage renal disease (ESRD) 1 . Insulin/insulin receptor substrate-1 (IRS1) signalling can increase nitric oxide (NO) production, which is mediated by the PI3K/Akt pathway, thereby increasing anti-inflammatory effects 2 . NO induces vasodilatation and inhibits podocyte apoptosis 3 . Diabetes can inhibit insulin/IRS1 signalling in mesangial and glomerular endothelial cells, probably through the protein kinase C (PKC) β2 pathway 2 .Vascular endothelial growth factor (VEGF)-A can activate the anti-apoptotic proteins survivin or Bcl-2, thus decreasing endothelial cell apoptosis 4 . Insulin enhances VEGF-A expression, which in turn leads to increased Akt and eNOS phosphorylation, thus protecting against renal cell apoptosis. Furthermore, in our previous study, diabetes could increase podocyte apoptosis in DKD via activation of PKCδ/p38 mitogen-activated protein (MAPK) to enhance Src homology-2 domain containing phosphatase-1 (SHP-1) expression, which in turn resulted in VEGF resistance 5 . Thus, it is likely that the loss of effect of insulin on glomeruli may contribute to the development of DKD.Incretins are the family of gut hormones including glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. Our recent study indicate...

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates Endothelial Inflammation and Microvascular Thrombosis in a Sepsis Mouse Model

“…One limitation of our study is that we did not establish a model of sepsis induced by real pathogens, which limits the application of our findings to patients in the clinical context. Another limitation is that we did not test linagliptin at a lower concentration; as low as 50 nM has shown protective effects in vitro [ 32 , 33 ]. Additional work is needed to investigate the potential toxicity or benefits of different linagliptin concentrations.…”

Mitochondria-targeted drugs for diabetic kidney disease

“…DPP-4 inhibitors can reduce inflammation and decrease MCP-1 levels ( Hung et al., 2020 ). Both DPP-4 and GLP-1 elicit vasotropic effects and decrease diabetes-induced oxidative stress in the glomerulus, ameliorating DKD ( Mima et al., 2020 ) ( Mima et al., 2012a ). Recent studies have shown that sitagliptin treatment activates the transcription factor cAMP response element-binding protein (CREB), which increases β cell mass or islet angiogenesis ( Samikannu et al., 2013 ).…”

“…We have reported that GLP-1 increased by DPP-4 inhibitors can activate adenylyl cyclase, promote cAMP production, and foster PKA activation, which subsequently induces serine phosphorylation of CREB ( Mima et al., 2012a ). Interestingly, linagliptin was shown to increase anti-oxidative stress effects in podocytes by increasing Nrf2 ( Mima et al., 2020 ).…”

Repositioning Linagliptin for the Mitigation of Cadmium-Induced Testicular Dysfunction in Rats: Targeting HMGB1/TLR4/NLRP3 Axis and Autophagy

“…Likewise, no hypoglycemia has been reported regarding linagliptin administration in normoglycemic animals, as seen in preclinical models of chronic kidney damage [ 27 ], inflammatory bowel disease [ 29 ], and an Aβ42-induced Alzheimer model [ 28 ]. Beyond its glucose modulating actions, linagliptin has demonstrated remarkable anti-inflammatory actions [ 27 , 29 ] and anti-apoptotic effects [ 30 , 31 ] in several pathological models in rodents. However, the potential ameliorative ability of linagliptin against cadmium-induced testicular injury has not been previously considered.…”