Involvement of Dipeptidyl Peptidase IV in Immune Complex–Mediated Glomerulonephritis

Shinosaki, Toshihiro; Kobayashi, Tatsuo; Kimura, Kazuhiro; Kurihara, Hidetake

doi:10.1038/labinvest.3780443

Cited by 9 publications

(10 citation statements)

References 31 publications

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“…Shinosaki et al (30) previously reported that monoclonal antibody against DPP-4 considerably reduced proteinuria and mesangial expansion via the suppression of the complement cascade in the rat Thy-1 model. Contrary to this report, we observed a nonsignificant trend toward reductions in glomerular injury and proteinuria in the present study.…”

Section: Discussionmentioning

confidence: 98%

Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury

Higashijima

Tanaka

Yamaguchi

et al. 2015

American Journal of Physiology-Renal Physiology

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Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic β-cells. DPP-4 inhibitors are now widely used for the treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.

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Section: Discussionmentioning

confidence: 98%

Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury

Higashijima

Tanaka

Yamaguchi

et al. 2015

American Journal of Physiology-Renal Physiology

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“…11 HMGB1, a nuclear protein that regulates gene transcription, is passively released after cell injury and has been implicated in tissue inflammation in animal models of kidney injury. 13,30 HMGB1 is a known ligand of TLR, which leads to the activation of NF-kB, ultimately increasing tissue inflammation. 12,31 We also found that renal expression of HMGB1 was decreased in mice given LC15-0444 treatment in this study.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

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Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFb1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-kB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.

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“…These results suggest a protective role for the neutralizing antibody of DPP-4 against complement-mediated tissue injury. 68 However, it is unclear whether similar modes of protection might be conferred by the enzymatic inhibition of DPP-4 using DPP-4 inhibitors and whether GLP-1 phenocopies these immune-modulating effects.…”

Section: Nondiabetic Chronic Kidney Diseasementioning

confidence: 99%

The potential for renoprotection with incretin-based drugs

Tanaka

Higashijima

Wada

et al. 2014

Kidney International

115

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Incretin-based drugs, i.e., glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are widely used for the treatment of type 2 diabetes. In addition to the primary role of incretins in stimulating insulin secretion from pancreatic β-cells, they have extra pancreatic functions beyond glycemic control. Indeed, recent studies highlight the potential beneficial effects of incretin-based therapy in diabetic kidney disease (DKD). Experimental studies using various diabetic models suggest that incretins protect the vascular endothelium from injury by binding to GLP-1 receptors, thereby ameliorating oxidative stress and the local inflammatory response, which reduces albuminuria and inhibits glomerular sclerosis. In addition, there is some evidence that GLP-1 receptor agonists and DPP-4 inhibitors mediate sodium excretion and diuresis to lower blood pressure. The pleiotropic actions of DPP-4 inhibitors are ascribed primarily to their effects on GLP-1 signaling, but other substrates of DPP-4, such as brain natriuretic peptide and stromal-derived factor-1α, may have roles. In this review, we summarize recent studies of the roles of incretin-based therapy in ameliorating DKD and its complications.

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Involvement of Dipeptidyl Peptidase IV in Immune Complex–Mediated Glomerulonephritis

Cited by 9 publications

References 31 publications

Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury

Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

The potential for renoprotection with incretin-based drugs

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