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Linagliptin unmasks specific antioxidant pathways protective against albuminuria and kidney hypertrophy in a mouse model of diabetes.

ABSTRACT: BACKGROUND: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. METHODS:DBA/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. RESULTS:In 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. CONCLUSIONS:Linagliptin 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.

SUBMITTER: Spencer NY

PROVIDER: S-EPMC6034861 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Linagliptin unmasks specific antioxidant pathways protective against albuminuria and kidney hypertrophy in a mouse model of diabetes.

Spencer Netanya Y NY Yang Zhihong Z Sullivan Jensyn Cone JC Klein Thomas T Stanton Robert C RC

PloS one 20180706 7

<h4>Background</h4>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.<h4>Methods</h4>DBA/2J mice (a well-characterized model of DKD) and glucose 6-phosphate dehydrogenase (G6PD) deficient mice (a model of imp ...[more]

PMID: 29979777

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Project description:Background:A link between selenium deficiency and inflammatory skin diseases have been noted by many, but this link is still not well understood. We have previously studied the efficacy of ceramide analogs, based on the fire ant venom Solenopsin A, against our psoriasis animal model. Treatment of animals with solenopsin analogs resulted in significantly improved skin as well as in a coordinate downregulation of selenoproteins, namely Glutathione Peroxidase 4 (GPX4). We thus hypothesize that ferroptosis may be a physiologic process that may protect the skin from both inflammatory and neoplastic processes.Methods:We analyze and compare gene expression profiles in the GEO database from clinical skin samples taken from healthy patients and psoriasis patients (both involved and noninvolved skin lesions). We validated the gene expression results against a second, independent, cohort from the GEO database.Results:Significant reduction in gene expression of GPX4, elevated expression of Nrf2 downstream targets, and expression profiles mirroring erastin-inhibition of Cystine/Glutamate Antiporter-System XC activity in psoriatic skin lesions, compared to both noninvolved skin and healthy patient samples, suggest an innately inducible mechanism of ferroptosis.Conclusions:We present data that may indicate selenoproteins, particularly GPX4, in resolving inflammation and skin cancer, including the novel hypothesis that the human organism may downregulate GPX4 and reactive oxygen (REDOX) regulating proteins in the skin as a way of resolving psoriasis and nonmelanoma skin cancer through increased reactive oxygen species. Further studies are needed to investigate ferroptosis as a possible physiologic mechanism for eliminating inflammatory and malignant tissues.General significance:This study provides a fresh framework for understanding the seemingly contradictory effects of selenium supplementation. In addition, it offers a novel explanation of how physiologic upregulation of ferroptosis and downregulation of selenoprotein synthesis may mediate resolution of inflammation and carcinogenesis. This is of therapeutic significance.

Dataset Information

Linagliptin unmasks specific antioxidant pathways protective against albuminuria and kidney hypertrophy in a mouse model of diabetes.

Publications

Linagliptin unmasks specific antioxidant pathways protective against albuminuria and kidney hypertrophy in a mouse model of diabetes.

Similar Datasets

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