DPP-4 Inhibitor Attenuates Toxic Effects of Indoxyl Sulfate on Kidney Tubular Cells

Abstract

Diabetic nephropathy is a common causative factor of chronic kidney disease (CKD). DPP-4 inhibitor has the ability to improve kidney function and renal microvasculature. In the present study, we investigate the deleterious effects of IS on proximal tubular cells and the protective role of DPP-4 inhibitor. Human kidney 2 (HK-2) cells were exposed to IS in the presence or absence of DPP-4 inhibitor. Effects of DPP-4 inhibitor on viability of HK-2 cells were determined by MTT assay. Reactive oxygen species (ROS) production was examined using fluorescent microscopy. Levels of cleaved caspase-3, transforming growth factor-beta (TGF-β), α-smooth muscle actin (α-SMA) and NF-kappaB p65 and phosphorylation of AKT and extracellular signal-regulated kinase (ERK) were detected by immunoblotting. Production of ROS and level of cleaved caspase-3 were increased by IS in a dose-dependent manner. The phosphorylation of AKT and ERK p65 were decreased alongside activation of NF-κB. Expression of TGF-β and α-SMA, were upregulated in IS-treated HK-2 cells. Treatment with DPP-4 inhibitor resulted in a significant increase in cell viability and a decrease of ROS production in IS-treated HK-2 cells. DPP-4 inhibitor restored IS-induced deactivations of AKT and ERK and inhibited activation of NF-κB in IS-treated HK-2 cells. Moreover, DPP-4 inhibitor could also attenuate IS-induced up-regulation of TGF-β and α-SMA expression. These findings suggest that DPP-4 inhibitor possesses anti-apoptotic activity to ameliorate the IS-induced renal damage, which may be partly attributed to regulating ROS/p38MAPK/ERK and PI3K-AKT pathways as well as downstream NF-κB signaling pathway.

Protective effect of sitagliptin against renal ischemia reperfusion injury in rats

“…However, in the mentioned article, the effects of sitagliptin against renal I/R injury in non-diabetic rats were not investigated. Also, Wang et al 46 reported that DPP-4 inhibitor attenuates toxic effects of indoxyl sulfate on kidney tubular cells. Joo et al 47 reported that DPP-4 IV inhibitor attenuates kidney injury in rat remnant kidney.…”

Sitagliptin attenuates inflammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition

“…It has been reported that the regulation of NF-κB was involved in the amelioration of inflammatory responses by DPP-4 inhibitor (25). Several studies also demonstrated that DPP-4 inhibitor has beneficial effects on cardiovascular system and gain the ability to improve renal microvasculature (26,27). However, the role of DPP-4 inhibition in ameliorating cardiovascular complication and potential anti-inflammatory properties during sepsis has not been largely investigated.…”

Linagliptin inhibits lipopolysaccharide-stimulated interleukin-6 production, intranuclear p65 expression, and p38 mitogen-activated protein kinase phosphorylation in human umbilical vein endothelial cells

“…Until now, six studies have reported the anti-inflammatory effects of DPP-4 inhibitors other than linagliptin in vitro [38][39][40][41][42][43], four of which involve leucocytes. Dai et al .…”

“…Another in vitro study examined proximal tubular cells (human kidney 2 cells) in this context. Wang et al showed that the antiapoptotic activity of diprotin A, a DPP-4 inhibitor, ameliorates indoxyl sulfate-induced renal damage, which may be partly attributed to the ROS/p38MAPK/ERK and phosphoinositide 3 kinase (PI3K)-AKT pathways [43]. These in vitro studies raised the possibility that almost all DPP-4 inhibitors, including linagliptin, possess anti-inflammatory functions that are independent of GLP-1.…”