Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats.
Dipeptidyl peptidase (DPP) IV inhibitors are probably beneficial for preventing diabetic complication and modulating glucagon-like peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine whether the DPP IV inhibitor LAF237 (vildagliptin) has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and nondiabetic rats were treated with an oral dose of 4 or 8 mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, active GLP-1 level, cAMP and 8-hydroxy-deoxyguanosine excretion, and GLP-1R, cleaved caspase 3, and transforming growth factor-β1 (TGF-β1) expression. LAF237 significantly decreased proteinuria, albuminuria, and urinary albumin/creatinine ratio, improved creatinine clearance, and dose-dependently inhibited interstitial expansion, glomerulosclerosis, and the thickening of the glomerular basement membrane in diabetic rats. It is noteworthy that LAF237 markedly down-regulated DPP IV activity and increased active GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating the GLP-1R and modulating cAMP. Renoprotection was also associated with a reduction in TGF-β1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-β1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keum-Am Dong, Jeonju 561-712, South Korea.
Wei Jing
WJ
Liu
Shu Hua
SH
Xie
Yu Ning
YN
Liu
Won
W
Kim
Heung Yong
HY
Jin
Sung Kwang
SK
Park
Yi Ming
YM
Shao
Tae Sun
TS
Park
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D000242:Cyclic AMP / Q000652:urine; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004435:Eating / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000473:pathology; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000218:Adamantane; D001786:Blood Glucose; D053148:Caspase 3; D000242:Cyclic AMP; D003849:Deoxyguanosine; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007328:Insulin; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D053773:Transforming Growth Factor beta1; C475520:1-(((3-hydroxy-1-adamantyl)amino)acetyl)-2-cyanopyrrolidine; C000593835:Glp1r protein, rat; C505410:Casp3 protein, rat