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

다국어 초록 (Multilingual Abstract)

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 Ι collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type Ι 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.

참고문헌 (Reference)

1 Cernea S, "Therapy in the early stage: incretins" 34 (34): S264-S271, 2011

2 Muskiet MH, "The gutrenal axis: do incretin-based agents confer renoprotection in diabetes?" 10 : 88-103, 2014

3 Hwang HJ, "The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms" 405 : 25-34, 2015

4 Lan HY, "TGF-β/Smad signaling in kidney disease" 32 : 236-243, 2012

5 Leask A, "TGF-beta signaling and the fibrotic response" 18 : 816-827, 2004

6 Meng XM, "Smad2 protects against TGF-beta/Smad3-mediated renal fibrosis" 21 : 1477-1487, 2010

7 Mori H, "Sitagliptin improves albuminuria in patients with type 2 diabetes mellitus" 5 : 313-319, 2014

8 Scirica BM, "Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus" 369 : 1317-1326, 2013

9 Packham DK, "Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database" 59 : 75-83, 2012

10 Ziyadeh FN, "Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator" 15 (15): S55-S57, 2004

11 Park CW, "Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice" 18 : 1227-1238, 2007

12 Kanasaki K, "Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocininduced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen" 63 : 2120-2131, 2014

13 Kodera R, "Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes" 54 : 965-978, 2011

14 Sung-Ho Kim, "Gemigliptin, a novel dipeptidyl peptidase 4 inhibitor: first new anti-diabetic drug in the history of Korean pharmaceutical industry" 대한약학회 36 (36): 1185-1188, 2013

15 Hendarto H, "GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases" 61 : 1422-1434, 2012

16 Mentlein R, "Dipeptidyl-peptidase IV (CD26): role in the inactivation of regulatory peptides" 85 : 9-24, 1999

17 Kodera R, "Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes" 443 : 828-833, 2014

18 Weber AE, "Dipeptidyl peptidase IV inhibitors for the treatment of diabetes" 47 : 4135-4141, 2004

19 Min HS, "Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction" 94 : 598-607, 2014

20 Liu WJ, "Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats" 340 : 248-255, 2012

21 Deacon CF, "Dipeptidyl peptidase IV inhibition as an approach to the treatment and prevention of type 2 diabetes: a historical perspective" 294 : 1-4, 2002

22 박철휘, "Diabetic Kidney Disease: From Epidemiology to Clinical Perspectives" 대한당뇨병학회 38 (38): 252-260, 2014

23 Fujita H, "DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria via up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy" 61 : 159-166, 2014

24 Jung GS, "Clusterin attenuates the development of renal fibrosis" 23 : 73-85, 2012

25 Chrysant SG, "Clinical implications of cardiovascular preventing pleiotropic effects of dipeptidyl peptidase-4inhibitors" 109 : 1681-1685, 2012

26 White WB, "Alogliptin after acute coronary syndrome in patients with type 2 diabetes" 369 : 1327-1335, 2013

27 Kim N, "Absorption, metabolism and excretion of [14C]gemigliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans" 44 : 522-530, 2014