Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

Hasan, Ahmed A.; Hocher, Berthold

doi:10.1530/jme-17-0005

Cited by 53 publications

(47 citation statements)

References 59 publications

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“…DPP4 was increased in broblasts isolated from patients with systemic sclerosis and were involved in the differentiation of broblasts into myo broblasts [38]. Such evidence supports the speculation that DPP4 participates in the regulation of cellular functions and the progression of disease pathologies [39].…”

Section: Discussionsupporting

confidence: 71%

Dipeptidyl Peptidase-4 Involved in Regulating Mitochondria Function in Cardiomyocytes through Nrf2 and PGC-1α Signaling

Lee

et al. 2020

Preprint

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Background: Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) and the detoxification ability of reactive intermediates. It will lead to mitochondrial damage and dysfunction, resulting in the dysfunction of bioenergetic control and loss of ATP production, which is contributed to the pathogenesis of cardiac diseases. Dipeptidyl peptidase-4 (DPP4) is a transmembrane glycoprotein ubiquitously expressed and has multifunctional properties. DPP4 inhibitors are a class of oral diabetes drugs that inhibit the enzyme activity. In addition to its enzymatic property, considerably less is known regarding the nonenzymatic function of DPP4.Methods: We knocked down DPP4 gene expression in cultured cardiomyocytes to exclude any external and enzymatic substrate effects and compared the response between DPP4 knockdown and wild-type cardiomyocytes in response to oxidative stress.Results: H2O2-induced oxidative stress-stimulated intracellular and mitochondrial ROS concentration led to the loss of mitochondrial function, ATP production, and increased Bax and cleaved PARP expression, resulting in the loss of cell viability in cardiomyocytes. Oxidative stress induced DPP4 expression. Knocking down DPP4 ameliorated H2O2-induced loss of cell viability by preserving mitochondrial bioenergy, reducing intracellular ROS production, alleviating apoptosis-associated protein expression. Knocking down DPP4 increased its capability against oxidative stress by enhancing Nrf2 and PGC-1α signaling, which is associated with preserving mitochondrial function.Conclusions: DPP4 is a mediator of oxidative stress. Knocking down DPP4 without any external substrate mediators increased the capability of cardiomyocytes against oxidative stress, which indicated that DPP4 mediated more than the enzymatic-dependent pathway.

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Section: Discussionsupporting

confidence: 71%

Dipeptidyl Peptidase-4 Involved in Regulating Mitochondria Function in Cardiomyocytes through Nrf2 and PGC-1α Signaling

Lee

et al. 2020

Preprint

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“…Other DPP-4 inhibitors have also demonstrated renoprotective effects in animal models of diabetic nephropathy, as reviewed elsewhere [18,19,73].…”

Section: Effects Of Linagliptin In Animal Models Of Kidney Diseasementioning

confidence: 99%

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

Kanasaki

2018

Clinical Science

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Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

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“…The glucose‐lowering effect of DPP4 inhibitors is mostly mediated by inhibition of islet DPP4 activity to protect the concentration of DPP4 substrates (GLP‐1 and GIP) from degradation and directly stimulates insulin secretion 51 . Recent studies suggest the renal benefits of DPP4 inhibitors in animal models of both diabetic and nondiabetic CKD 14,15 . For example, DPP4 inhibitor linagliptin was found to alleviate albuminuria and delay the progression of tubulointerstitial injury in mice with 5/6 nephrectomy (5/6Nx) 14,18 .…”

Section: Discussionmentioning

confidence: 99%

Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3‐dependent mitochondrial homeostasis through SDF‐1α/CXCR4 pathway

Zhang

Dong

et al. 2020

FASEB j.

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Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase‐4 (DPP4) inhibitors are widely used antihyperglycemic agents that exert renal protective and positive effects against mitochondrial dysfunction in diabetic kidney disease (DKD). However, their underlying mechanism remains unclear. In this study, DPP4 upregulation, mitochondrial fragmentation, and altered mitochondrial dynamics‐associated protein expression were observed in the tubules of DBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin‐stimulated tubular cells. The inhibition of DPP4 by sitagliptin (Sita) ameliorated these mitochondrial perturbations both in vivo and in vitro, whereas DPP4 overexpression aggravated mitochondrial fusion‐fission disorder and tubular cell injury in albumin‐treated HK‐2 cells. Downstream of DPP4, the SDF‐1α/CXCR4 pathway was significantly suppressed in diabetic tubules. After Sita treatment, this signaling pathway was restored, and the mitochondrial dynamics was improved. Furthermore, a direct interaction between STAT3 and OPA1 was found in the mitochondria of tubular cells, and this effect was weakened by overloading albumin and by CXCR4 siRNA treatment, suggesting a possible link between DPP4‐mediated SDF‐1α/CXCR4/STAT3 signaling and mitochondrial dysfunction in diabetic tubular cells. The results suggest that a novel mechanism links the DPP4 enzyme to impaired mitochondrial dynamics homeostasis during tubular injury in DKD and highlight that the SDF‐1α/CXCR4/STAT3 signaling pathway could become a potential target for managing DKD.

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Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

Cited by 53 publications

References 59 publications

Dipeptidyl Peptidase-4 Involved in Regulating Mitochondria Function in Cardiomyocytes through Nrf2 and PGC-1α Signaling

Dipeptidyl Peptidase-4 Involved in Regulating Mitochondria Function in Cardiomyocytes through Nrf2 and PGC-1α Signaling

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3‐dependent mitochondrial homeostasis through SDF‐1α/CXCR4 pathway

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