Evogliptin, a Dipeptidyl Peptidase-4 Inhibitor, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

Renal fibrosis is considered to be the final common outcome of chronic kidney disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated protective effects against diabetic kidney disease. However, the anti-fibrotic effect of evogliptin, a DPP-4 inhibitor, has not been studied. Here, we report the beneficial effects of evogliptin on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Evogliptin attenuated UUO-induced renal atrophy and tubulointerstitial fibrosis. Immunohistochemistry and Western blotting demonstrated that evogliptin treatment inhibits pro-fibrotic gene expressions and extracellular matrix production. In vitro findings showed that the beneficial effects of evogliptin on renal fibrosis are mediated by inhibition of the transforming growth factor-β/Smad3 signaling pathway. The present study demonstrates that evogliptin is protective against UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of kidney disease of non-diabetic origin.

Gemigliptin Attenuates Renal Fibrosis Through Down-Regulation of the NLRP3 Inflammasome

BACKGROUND: The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.METHODS: We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins.RESULTS: Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with thein vivoresults, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.CONCLUSION: The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.

Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

BACKGROUND: Renal tubulointerstitial fibrosis is a common feature of the final stage of nearly all cause types of chronic kidney disease. Although classic peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on diabetic nephropathy, much less is known about their direct effects in renal fibrosis. This study aimed to investigate possible beneficial effects of lobeglitazone, a novel PPARγ agonist, on renal fibrosis in mice. METHODS: We examined the effects of lobeglitazone on renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) induced renal fibrosis mice. We further defined the role of lobeglitazone on transforming growth factor (TGF)-signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study. RESULTS: Through hematoxylin/eosin and sirius red staining, we observed that lobeglitazone effectively attenuates UUO-induced renal atrophy and fibrosis. Immunohistochemical analysis in conjunction with quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that lobeglitazone treatment inhibited UUO-induced upregulation of renal Smad-3 phosphorylation, α-smooth muscle actin, plasminogen activator inhibitor 1, and type 1 collagen. In vitro experiments with rat mesangial cells and NRK-49F renal fibroblast cells suggested that the effects of lobeglitazone on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway. CONCLUSION: The present study demonstrates that lobeglitazone has a protective effect on UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of non-diabetic origin renal disease.

Renoprotective Effect of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Streptozotocin-Induced Type 1 Diabetic Mice

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice. METHODS: Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis. RESULTS: Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation. CONCLUSION: Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.

Cilostazol inhibits insulin-stimulated expression of sterol regulatory binding protein-1c via inhibition of LXR and Sp1

Hepatic steatosis is common in obese individuals with hyperinsulinemia and is an important hepatic manifestation of metabolic syndrome. Sterol regulatory binding protein-1c (SREBP-1c) is a master regulator of lipogenic gene expression in the liver. Hyperinsulinemia induces transcription of SREBP-1c via activation of liver X receptor (LXR) and specificity protein 1 (Sp1). Cilostazol is an antiplatelet agent that prevents atherosclerosis and decreases serum triglyceride levels. However, little is known about the effects of cilostazol on hepatic lipogenesis. Here, we examined the role of cilostazol in the regulation of SREBP-1c transcription in the liver. The effects of cilostazol on the expression of SREBP-1c and its target genes in response to insulin or an LXR agonist (T0901317) were examined using real-time RT-PCR and western blot analysis on cultured hepatocytes. To investigate the effect of cilostazol on SREBP-1c at the transcriptional level, transient transfection reporter assays and electrophoretic mobility shift assays (EMSAs) were performed. Cilostazol inhibited insulin-induced and LXR-agonist-induced expression of SREBP-1c and its downstream targets, acetyl-CoA carboxylase and fatty acid synthase, in cultured hepatocytes. Cilostazol also inhibited activation of the SREBP-1c promoter by insulin, T0901317 and Sp1 in a luciferase reporter assay. EMSA analysis showed that cilostazol inhibits SREBP-1c expression by repressing the binding of LXR and Sp1 to the promoter region. These results indicate that cilostazol inhibits insulin-induced hepatic SREBP-1c expression via the inhibition of LXR and Sp1 activity and that cilostazol is a negative regulator of hepatic lipogenesis.