Diabetes Metab J.  2020 Feb;44(1):186-192. 10.4093/dmj.2018.0271.

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

  • 1Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea. kpark@knu.ac.kr, exc4932@hanmail.net
  • 2Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Korea.
  • 3BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Korea.
  • 4New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.


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.


Dipeptidyl-peptidase IV inhibitors; Kidney failure, chronic; Transforming growth factor beta

MeSH Terms

Blotting, Western
Diabetic Nephropathies
Dipeptidyl-Peptidase IV Inhibitors
Extracellular Matrix
Gene Expression
In Vitro Techniques
Kidney Diseases
Kidney Failure, Chronic
Renal Insufficiency, Chronic
Transforming Growth Factor beta
Ureteral Obstruction*
Dipeptidyl-Peptidase IV Inhibitors
Transforming Growth Factor beta


  • Fig. 1 Effects of evogliptin (Evo) on renal fibrosis and pro-fibrotic gene expression in kidneys of unilateral ureteral obstruction (UUO) mice. A UUO kidney from a mouse at day 11. (A) Representative images of hematoxylin and eosin (H&E) and Sirius red staining of kidney tissue sections from control (CON) mice and UUO mice treated with (300 mg/kg) or without Evo. The number of atrophic tubules was determined by measuring the amount of abnormal irregular and dilated tubular basement membranes in H&E-stained sections under high power magnification (×200). Areas of positive staining with Sirius red were quantitated by computer-based morphometric analysis. All morphometric data were normalized against the corresponding val-ues in CON animals. Data in all bar graphs are expressed as fold increases relative to the CON (n=6 in each group). (B) Representative images of immunohistochemical staining for phosphorylated-Smad3 (p-Smad3), plasminogen activator inhibitor 1 (PAI-1), fibronectin, α-smooth muscle actin (α-SMA), and type I collagen in kidney tissue sections from CON mice or UUO mice treated with (300 mg/kg) or without Evo (n=6 in each group). Areas of positive staining with p-Smad3, PAI-1, fibronectin, α-SMA, and type I collagen antibodies were quantitated by computer-based morphometric analysis. Data are the mean±standard error of the mean (SEM) of five random fields from each kidney. (C) Representative western blot analysis of p-Smad3, total-Smad3 (t-Smad3), PAI-1, fibronectin, α-SMA, and type I collagen protein level in UUO kidneys from mice treated with (300 mg/kg) or without Evo (n=6 in each group). Data in the bar graphs are the mean±SEM. NS, not significant. aP<0.05, bP<0.01, cP<0.001.

  • Fig. 2 Effects of evogliptin (Evo) on transforming growth factor-β (TGF-β)-induced pro-fibrotic gene expression in cultured kidney cell lines. Representative Western blot analysis of phosphorylated-Smad3 (p-Smad3), total-Smad3 (t-Smad3), plasminogen activator inhibitor 1 (PAI-1), fibronectin, α-smooth muscle actin (α-SMA), and type I collagen protein level in TGF-β-stimulated (A) human proximal renal tubular epithelial (HK-2) cells and (B) normal rat kidney fibroblasts (NRK-49F) cells. Cells were incubated with TGF-β (5 ng/mL) treated with (100 or 200 µg/mL) or without Evo co-treatment for 24 hours. Data are the mean±standard error of the mean (SEM) of three independent measurements. (C) Effects of Evo on PAI-1 promoter activity in NRK-49F and NRK-52E cells. Cells were treated with TGF-β (5 ng/mL) treated with (100 µg/mL) or without Evo co-treatment for 24 hours. Data are the mean±SEM of three independent measurements. NS, not significant; Luc, luciferase. aP<0.05, bP<0.01, cP<0.001.


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