Abstract
BackgroundDipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects on diabetic kidney disease (DKD) via specific antioxidant pathways. The DPP-4 inhibitor, linagliptin, was evaluated with the hypothesis that DPP-4 inhibition would ameliorate the development of DKD in a glucose-independent manner by altering specific antioxidant function.MethodsDBA/2J mice (a well-characterized model of DKD) and glucose 6-phosphate dehydrogenase (G6PD) deficient mice (a model of impaired antioxidant function) were evaluated. Diabetes was induced by streptozotocin. Mice were divided into: diabetic (DM), diabetic+linagliptin (DM+Lina), and non-diabetic control and treated for 12 weeks.ResultsIn DBA/2J mice, there was no difference in body weight and blood glucose between DM and DM+Lina groups. Linagliptin ameliorated albuminuria and kidney hypertrophy in DM DBA/2J mice and specifically increased the mRNA and protein levels for the antioxidants catalase and MnSOD. In G6PD deficient mice, however, increases in these mRNA levels did not occur and linagliptin renoprotection was not observed. Linagliptin also ameliorated histological trends toward mesangial expansion in wild-type mice but not in G6PD deficient mice.ConclusionsLinagliptin renoprotection involved glucose-independent but antioxidant-enzyme-system-dependent increases in transcription (not just increased protein levels) of antioxidant proteins in wild-type mice. These studies demonstrate that an intact antioxidant system, in particular including transcription of catalase and MnSOD, is required for the renoprotective effects of linagliptin.
Highlights
Diabetic kidney disease (DKD) continues to rise at epidemic rates throughout the world despite current treatments [1, 2]
The Dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, was evaluated with the hypothesis that DPP-4 inhibition would ameliorate the development of DKD in a glucose-independent manner by altering specific antioxidant function
In DBA/2J mice, there was no difference in body weight and blood glucose between DM and diabetic +linagliptin (DM+Lina) groups
Summary
Diabetic kidney disease (DKD) continues to rise at epidemic rates throughout the world despite current treatments [1, 2]. DPP-4 inhibitors (such as linagliptin, saxagliptin, sitagliptin, etc.) have shown promise for providing renal protection in animal models [3,4,5] and humans [6,7,8]. Regardless of the success of the large clinical trials, understanding the mechanisms by which DPP-4 inhibitors provide renal protection in animals may provide new targets for drug development. With regards to renoprotective mechanisms, animal studies with DPP4 inhibitors have shown improved pathologic markers such as prevention of glomerulosclerosis and interstitial fibrosis [3, 4, 10]. Dipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects on diabetic kidney disease (DKD) via specific antioxidant pathways. The DPP-4 inhibitor, linagliptin, was evaluated with the hypothesis that DPP-4 inhibition would ameliorate the development of DKD in a glucose-independent manner by altering specific antioxidant function
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