Cereals

The purpose of this study was to characterize neuropeptide Y (NPY) overflow and metabolism from isolated skeletal muscle arterioles of female rats. Gastrocnemius first-order arterioles were removed from young (2 months), young adult (6 months) and middle-aged (12 months) F344 female rats. Arterioles were isolated, cannulated and pressurized in a microvessel bath with field stimulation electrodes. NPY overflow from isolated arterioles was assessed at 0 s and 30 s post-field stimulation. Dipeptidyl peptidase IV (DPPIV) activity was quantified via fluorometric assay of whole vessel homogenate. In young adult and middle-aged rats, NPY overflow increased 0 s and 30 s following field stimulation. In young adult rats, DPPIV inhibition resulted in an increase in NPY overflow at 30 s, while middle-aged rats had no increase in NPY overflow with DPPIV inhibition (P <0.05). DPPIV activity was influenced by factors such as age, vessel type, and endothelium (P <0.05). The present data suggest that DPPIV plays a significant role in modulating the actions of NPY in arterioles of young adult females; however, this role appears to diminish with age.

Evaluation of anti-diabetic and antihypertensive activity of Phoenix sylvestris (L.)Roxb leaves extract and quantification of biomarker Quercetin by HPTLC

Autophagy-associated signal pathways of functional foods for chronic diseases

Registration:PROSPERO: CRD42020210645Introduction:We aimed to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older patients with type 2 diabetes with inadequate glycaemic control.Methods:We included randomized controlled trials (RCTs) in older (⩾65 years) patients with type 2 diabetes. The intervention group was randomized to treatment with any DPP-4 inhibitors. A systematic search in MEDLINE and Embase was performed in December 2020. For assessing the risk of bias, RoB 2 tool was applied. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We pooled outcomes using random effects meta-analyses.Results:We identified 16 RCTs that included 19,317 patients with a mean age of greater than 70 years. The mean HbA1c level ranged between 7.1 and 10.0 g/dl. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly [risk ratio (RR) 1.04; 95% confidence interval (CI) 0.89–1.21]. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia (RR 1.08; 95% CI 1.01–1.16), but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas (RR 0.88; 95% CI 0.75–1.04). DPP-4 inhibitors probably reduce the risk for hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis.Conclusion:There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase hypoglycaemia risk. Second-line therapy in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case second-line treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas.Plain language summarySafety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetesIntroduction:We performed the review to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older type 2 diabetes patients with blood sugar outside the normal level.Methods:To answer the question, we searched various electronic databases. We included studies in older (⩾65 years) patients with type 2 diabetes that assessed the safety of DPP-4 inhibitors. The data from the different studies were quantitatively summarized using statistical methods. We assessed the quality of the data to judge the certainty of the findings.Results:We identified 16 studies that included 19,317 patients with a mean age greater than 70 years. The average blood sugar level of patients in the included studies was slightly or moderately increased. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia, but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas. DPP-4s probably reduce the risk of hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis.Conclusion:There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase the risk that blood sugar falls below normal. Adding DPP-4 inhibitorss to standard care in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case additional treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas.

Background It is not known which type 2 diabetes mellitus (T2DM) patients would most benefit from dipeptidyl peptidase-4 (DPP-4) inhibitor treatment. We aimed to investigate the predictors of response to DPP-4 inhibitors considering degree of DPP-4 inhibition.Methods This study is a post hoc analysis of a 24-week, randomized, double-blind, phase III trial that compared the efficacy and safety of a DPP-4 inhibitor (gemigliptin vs. sitagliptin) in patients with T2DM. Subjects were classified into tertiles of T1 <65.26%, T2=65.26%–76.35%, and T3 ≥76.35% by DPP-4 inhibition. We analyzed the change from baseline in glycosylated hemoglobin (HbA1c) according to DPP-4 inhibition with multiple linear regression adjusting for age, ethnicity, body mass index, baseline HbA1c, and DPP-4 activity at baseline.Results The mean age was greater in the high tertile group compared with the low tertile group (T1: 49.8±8.3 vs. T2: 53.1±10.5 vs. T3: 55.3±9.5, P<0.001) of DPP-4 inhibition. Although HbA1c at baseline was not different among tertiles of DPP-4 inhibition (P=0.398), HbA1c after 24-week treatment was lower in the higher tertile compares to the lower tertile (T1: 7.30%±0.88% vs. T2: 7.12%±0.78% vs. T3: 7.00%±0.78%, P=0.021). In multiple regression analysis, DPP-4 enzyme inhibition rate was not a significant determent for HbA1c reduction due to age. In subgroup analysis by tertile of DPP-4 inhibition, age was the only significant predictor and only in the highest tertile (R2=0.281, B=–0.014, P=0.024).Conclusion This study showed that HbA1c reduction by DPP-4 inhibitor was associated with increasing age, and this association was linked with higher DPP-4 inhibition.

Heart failure is a major co-morbid association of diabetes mellitus. The incidence of heart failure in diabetic vs. control subjects is 2- to 3-fold greater in every decade of life.1 Similar data on prevalence have also been observed in the Framingham study.2 Conversely, diabetes represents a major co-morbidity in patients with heart failure. In both clinical trials and registries of heart failure patients, between 24% and 44% have known diabetes mellitus.3 A key epidemiological issue in the context of discussion of therapies for diabetes and the associated risk of heart failure is the impact of glycaemic control on heart failure risk. Both UKPDS4 and a large cohort investigated by Iribarren et al.5 have demonstrated a close positive linear relationship between haemoglobin A1c levels and rate of heart failure development. Specifically, poorest glycaemic control was associated with greatest risk of heart failure. However, studies such as UKPDS demonstrated that more intensive glycaemic control was not associated with reduced development of heart failure.6 More contemporaneous meta-analyses have supported this observation,7 albeit potentially driven by drug treatments such as thiazolidinediones which may contribute to heart failure development. Based on pre-clinical and early clinical work, dipeptidyl peptidase-4 (DPP-4) inhibitors should, in theory, have beneficial rather than adverse effects on progression of LV remodelling and therefore delay development of symptomatic heart failure8 (Figure 1). Dipeptidyl peptidase-4 is involved in the enzymatic breakdown of glucagon-like peptide (GLP)-1; thus, DPP-4 inhibition augments circulating GLP-1 levels, which appears to have beneficial effects upon the heart in animal models as well as in the post-myocardial infarction and established heart failure settings in man.9 DPP-4 stimulates activation of proinflammatory cytokines,9 independent drivers of progression of LV systolic dysfunction due to their prohypertrophic and profibrotic effects.10 Inhibition of DPP-4 augments circulating levels of soluble-derived factor (SDF)-1 α,9 a stimulant of bone marrow production of erythroid precursor cells, which should contribute to improved vascular and myocardial function. Finally, DPP-4 inhibition should direct BNP metabolism towards an increase in active BNP rather than biologically inactive BNP precursor fragments.9 Pre-clinical studies with DPP-4 inhibitors in animal models of LV systolic dysfunction11 support a beneficial effect on LV remodelling and survival in comparison with controls. Published and ongoing major cardiovascular outcome trials with DPP-4 inhibitors are summarized in Table 1. Three major DPP-4 inhibitor trials have recently reported, all with implications for heart failure, and these are examined in greater detail below. The SAVOR-TIMI 53 trial compared the DPP-4 inhibitor, saxagliptin, with placebo in the setting of patients with a history of, or who are at risk of, cardiovascular events.12 There was no overall effect of saxagliptin vs. placebo on the primary endpoint of time to first event of cardiovascular death, myocardial infarction, or ischaemic stroke. However, patients in the saxagliptin group were more likely to be hospitalized for heart failure than those in the placebo group [3.5 vs. 2.8%, hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.07–1.51, P = 0.007]. A Kaplan–Meier plot of accrual of heart failure hospitalizations over time showed an early divergence of the curves which continued to diverge slightly beyond the first 180 days of treatment.13 A Forrest plot of key baseline variables that may influence risk of heart failure hospitalization according to treatment did not demonstrate any heterogeneity, with all pre-defined subgroups trending towards an excess of primary endpoint events with saxagliptin vs. placebo. One exception may be baseline plasma NT-proBNP levels. In those patients within the highest BNP quartile (333–46627 pg/mL), 10.9% of saxagliptin and 8.9% of placebo patients had a hospitalization for heart failure (P = 0.024). The EXAMINE study assessed the DPP-4 inhibitor, alogliptin, in patients who had recently had an acute coronary syndrome.14 As with saxagliptin in SAVOR, there was no significant effect of this class on the primary endpoint (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke). In EXAMINE, 3.9% of alogliptin-treated and 3.3% of placebo-treated patients had a hospitalization for heart failure (HR 1.19, 95% CI 0.89–1.58, P = NS).15 This was a pre-defined exploratory endpoint that was independently adjudicated. In EXAMINE, 28% of patients had a history of congestive heart failure at baseline. The primary EXAMINE endpoint was reduced with alogliptin vs. placebo, HR 0.82, P = 0.2015, in these patients. Data on recurrent heart failure hospitalizations within this subgroup have not as yet been reported. The Vildagliptin In Ventricular Dysfunction Diabetes (VIVIDD) trial has been presented16 but not yet published. All patients in VIVIDD had evidence of symptomatic systolic heart failure with an LVEF <35% as well as diabetes requiring glucose-lowering therapy. There was no difference in adjudicated heart failure events between vildagliptin (n = 128, 18%) and placebo (n = 125, 17.6%) patients over the 52 weeks of the study. The primary endpoint of the VIVIDD study was change in LVEF, with no difference observed between treatment groups (+0.54, 95% CI –1.97 to 3.06, P = 0.67). Interestingly, plasma BNP levels were reduced in both groups: vildagliptin, ratio of 0.72 vs. baseline; placebo, 0.86 vs. baseline. Somewhat surprisingly, LV diastolic and systolic volumes were both increased with vildagliptin compared with placebo. Our group recently performed a meta-analysis of heart failure outcomes with DPP-4 inhibitors, including the above studies. Forest plots of these data, comparing DPP-4 inhibitor with placebo and an active comparator, are shown in Figure 2. A sensitivity analysis was also undertaken, with thiazolidenediones included and excluded as comparator. With thiazolidenediones included, the risk ratio for heart failure with DPP-4 inhibitors was 0.80, 95% CI 0.35–1.81, P = 0.59. With thiazolidenediones removed as comparator, the risk ratio for heart failure was 1.15, 95% CI 1.00–1.33, P = 0.04. It is not entirely certain whether DPP-4 inhibitors directly or even indirectly cause heart failure, but if one accepts the premise that this is the case, then a number of potential explanations need to be considered. It is entirely plausible that the increase in heart failure events observed, particularly in SAVOR,12 represents the play of chance. There is a long history of ‘play of chance’ influencing cardiovascular trials. This is particularly true of subgroup analysis, but would equally apply to analysis of ‘off-target’ effects of drugs.17 Nevertheless, there are hints with DPP-4 inhibitors that this may not be the case, especially given the numerical increase in events in EXAMINE14 and the odd remodelling effects of vildagliptin in VIVIDD.16 Furthermore, there was an excess (not significant) of all-cause mortality events with vildagliptin amongst patients in VIVIDD.24 Although SAVOR and EXAMINE were large trials and baseline characteristics appear to be well balanced, it is certainly possible that there were imbalances at baseline between groups, which may have led to an increase in risk of heart failure hospitalization with the DPP-4 inhibitor. Specifically, there may be imbalances in background medications that are known to retard heart failure progression, such as ACE inhibitors. It would certainly be prudent to look at the patients who did have a heart failure hospitalization to see if there are baseline imbalances within this specific subgroup. Hypoglycaemia stimulates the sympathetic and renin–angiotensin–aldosterone systems and, thus, with chronic stimulation, may have adverse consequences including progression to symptomatic heart failure. However, the increase in rates of hypoglycaemia in both SAVOR and EXAMINE were very modest compared with the placebo group. An increase in relative risk for hypoglycaemia with saxagliptin in SAVOR was noted in patients on background sulfonylureas.12 However, when this subgroup was examined, there was no increase in risk of heart failure hospitalization with saxagliptin.13 Similarly, in EXAMINE, differences in hypoglycaemia were very minor between the alogliptin and placebo groups.14 Marney et al.18 suggested that sitagliptin interacted with high-dose enalapril to increase rather than decrease blood pressure levels in metabolic syndrome patients. This was associated with an increase in heart rate and plasma norepinephrine levels that was significant at the highest dose of enalapril. The mechanisms underlying this interaction are unclear but may relate to blockade of the peptides substance P and/or neuropeptide Y with DPP-4 inhibitors, leading to sympathetically mediated vasoconstriction. Similarly, Jackson et al.19 demonstrated that, in a renal perfusion model, enhancement of angiotensin II-mediated constrictor responses due to increasing neuropeptide Y administration could be exacerbated by sitagliptin and blocked if sitagliptin is given with a neuropeptide Y inhibitor. If the above are correct, then attention to heart rate and blood pressure responses in the major DPP-4 outcome trials would be of considerable interest. However, an analysis of earlier, much smaller saxagliptin studies20 suggested that (either as monotherapy or in combination) there was little impact on blood pressure with the DPP-4 inhibitor in comparison with placebo or metformin. The recent major DPP-4 inhibitor outcome studies have raised the hypothesis that heart failure may be precipitated and/or exacerbated with the use of these agents in the management of patients with diabetes. This is surprising given that preceding DPP-4 inhibitor data suggested potential for theoretical benefit with regard to HF, on the basis of the mechanisms outlined above.8, 9 This may represent play of chance and/or imbalances across study groups, but, if real, mechanisms urgently need to be elucidated. Until more data are available, guideline recommendations should be followed, but undoubtedly greater vigilance should be applied to recognizing the development of clinically significant HF in DPP-4 inhibitor-treated patients, including careful clinical assessment of heart failure symptoms and signs, together with (as required) ancillary objective assessments of heart failure status including measurement of plasma BNP levels and echocardiography. Two large-scale, placebo-controlled outcome trials, TECOS (with sitagliptin) and CARMELINA (with linagliptin), are due to report in the next few years, which should provide important data to support or refute the above hypothesis. In the meantime, a mechanistic explanation for this potential link should be further explored. Conflict of interest: none declared.

Expression of dipeptidylpeptidase 4 (DPP-4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP-4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP-4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). Expression of DPP-4 in skin biopsy samples and dermal fibroblasts was analyzed by real-time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP-4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). The expression of DPP-4 and the number of DPP-4-positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)-dependent manner. DPP-4-positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ-induced ERK signaling. DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (P < 0.0001 versus wild-type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft-versus-host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. DPP-4 characterizes a population of activated fibroblasts and shows that DPP-4 regulates TGFβ-induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well-tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.

Although functional foods are currently regulated the same as conventional foods by the US Food and Drug Administration (FDA) there is some concern that they should not be. One concern is whether functional foods can/should carry the same type of health and nutrition labeling claims as conventional foods. For example, the type of nutrient content claim that describes a level of the nutrient such as "good or excellent source" presents a problem for functional foods since these claims relate back to a standard value for nutrients (the daily value or DV). At this time the bioactive or functional components in a functional food do not have daily values so they could not take advantage of this type of claim. Structure/function claims are also at issue since they are required to relate to the food's attributes of taste, aroma, and nutritive value, rather than attributes of functionality (which would pertain to functional foods). There appear to be three categories of issues concerning the regulation of functional foods: safety; efficacy; and their effect on the overall diet. Since bioactive components can be synthesized or extracted and concentrated, the concern is that the amounts of these substances in functional foods might reach levels which are actually injurious to health or they may negate beneficial effects of substances in the same food. Most people/organizations consider that functional foods need to document their functionality. This means that unlike conventional foods, all functional foods, by definition, would have to apply for a health claim. Finally, the long term overarching concern is what will be the impact of a functional food-driven market on overall health. It is of interest to see how the regulatory environment for functional foods evolves in the next few years and what impact that environment has on the future of these foods.

Antioxidant and anti-diabetic activities in commercial and homemade pomegranate molasses in Lebanon

Is There Evidence of Any Safety Differences Among DPP-4 Inhibitors in the Treatment of People with Type 2 Diabetes Mellitus and Reduced GFR Due to Chronic Kidney Disease?

In recent years, functional foods and bioactive components in foods have drawn a lot of attention as well as interest of food scientists, nutritionists, health professionals, and consumers. The advent of this new food category has been facilitated by increasing scientific knowledge about the metabolic and genomic effects of diet and specific dietary components on human health. The relationship between health and diet is well known and it is a main key for prevention of variety of diseases. Milk is considered as a very good source of bioactive components and it has been known to contain macro- as well as micronutrients of high nutritional and therapeutic value. Also, bioactive components have been exploited from milk and dairy products for application in functional foods and for potential pharmaceutical use. Biologically active compounds guard neonates and adults against pathogens and illnesses. Some major bioactive components of milk are derived from caseins, whey proteins, lipids, lactoferrine, vitamins, immunoglobulins and growth factors. The aim of this paper was to provide an overview and explain the health effects of already known and recently detected bioactive components derived from bovine milk on humans.

Calcific aortic valve disease (CAVD) is characterized by endothelial dysfunction, fibrosis, and osteogenic calcification, yet the molecular mechanisms driving disease progression remain incompletely understood, and no pharmacological therapies are currently available. Reduced endothelial ILK (integrin-linked kinase) expression has been implicated in CAVD, but its downstream effectors remain undefined. To explore the direct role of ILK in CAVD development, we used a mouse model in which ILK is conditionally deleted from endothelial cells (endothelial cell-specific ILK conditional knockout). DPP4 (dipeptidyl peptidase 4) expression and activity were examined in human aortic valve tissue and plasma from patients with and without CAVD as a potential therapeutic target. Mechanistic studies were performed in human valvular endothelial cells subjected to ILK silencing, with or without pharmacological or genetic DPP4 inhibition. In vivo, endothelial cell-specific ILK conditional knockout mice were treated with the DPP4 inhibitor sitagliptin, and valvular, cardiac function, and remodeling were assessed. DPP4 expression was increased in circulation and in the aortic valves of patients with CAVD and was inversely correlated with ILK levels, with predominant localization to valvular endothelial cells. ILK silencing in human valvular endothelial cells increased DPP4 expression and enzymatic activity, promoted endothelial-to-mesenchymal transition, and induced osteogenic reprogramming; these effects were attenuated by DPP4 inhibition. Endothelial ILK deletion in mice recapitulated CAVD features, including inflammation, valve thickening, calcification, and cardiac remodeling, all of which were associated with increased DPP4. Sitagliptin treatment mitigated disease severity. Mechanistically, sitagliptin inhibited NF-κB (nuclear factor kappa B)-driven DPP4 upregulation caused by ILK loss. These findings identify DPP4 as a key downstream effector linking endothelial ILK deficiency to inflammation, endothelial-to-mesenchymal transition, and calcific remodeling in CAVD and support DPP4 inhibition as a potential disease-modifying strategy to slow disease progression.

Inhibition of dipeptidyl peptidase IV prevents high fat diet-induced liver cancer angiogenesis by downregulating chemokine ligand 2

Background and Aims The increasing prevalence rate of end-stage renal disease (ESRD) has emerged as a global health burden. Peritoneal dialysis (PD) possesses the survival and convenient advantage for ESRD during the first 2 years of dialysis treatment. However, long-term PD and hyperglycemia have been identified to frequently result in peritoneal fibrosis (PF) as subsequently to lead the failure of peritoneal function. Therefore, how to prevent PF is an important issue, especially in diabetic ESRD patients. Method To explore the effective protection in PD patients, Taiwan National Health Insurance Research Database was utilized to conduct the retrospective population-based cohort study from 1997 to 2013. A total of 19,828 diabetic ESRD patients with PD were analyzed the incidence of PD failure in the user and nonuser of dipeptidyl peptidase-4 (DPP4) inhibitors. On the other hand, the pathological role of DPP4 was further verified by cellular model and animal model of PF induced by chlorhexidine gluconate (CG). Results The rate of PD failure was significantly lower in diabetic ESRD patients with than without receiving DPP4 inhibitors (p&amp;lt;0.0001). Among all collected types of antidiabetic drugs, diabetic ESRD patients with DPP4 inhibitors treatment had the lowest rate of PD failure. In cellular study, the high concentration of glucose induced the increase of DPP4 protein levels, accumulating with the epithelial–mesenchymal transition (EMT), inflammation and the generation of oxidative stress in the mesothelial cells. However, sitagliptin treatment remarkably suppressed high concentration of glucose-inducing cellular damage. Additionally, in vivo study, sitagliptin treatment significantly decreased DPP4 activity, reversed EMT process via attenuating TGF-β/ Smad3 axil, ameliorated angiogenesis, reduced oxidative stress generation and inflammation through inhibiting NF-κB/ MyD88 signaling, followed by protected peritoneal integrity and function against CG-inducing PF in rats. Conclusion DPP4 contributed to the peritoneal fibrosis and functional impairment, whereas DPP4 inhibitors were suggested as a clinical protective strategy for extending PD. Figure:

Background and Aims Crescent formation is a severe glomerular damage in the pathogenesis of different kidney diseases. However the exact pathomechanism of crescent formation is unclear up to now. In human kidney biopsies we observed high dipeptidyl peptidase 4 (DPP4) expression in early crescent formation. Therefore, we investigated the potential involvement of DPP4 in the pathogenesis of crescentic anti-GBM nephritis in a rat model using a DPP4- inhibitor independent of his present use in the treatment of type 2 diabetes. Method Anti-GBM nephritis was induced in Wistar Kyoto rats for investigation of short and long term effects of the DPP4- inhibitor linagliptin treatment (3 mg/kg bw). In the short term experiment (endpoint 2 weeks) linagliptin treatment was started either with model induction or one week later. In the long term experiment (endpoint 8 weeks) linagliptin treatment was started either on day 0 or on week 4. In both experiments we included an untreated healthy and anti-GBM nephritic group. All groups consisted of 11 animals. Kidney function was monitored on weeks 1, 2, 3, 5 and 8. Kidney tissue was used to determine DPP4 expression and activity, morphologic changes and mRNA expression. Results Similarly to our observation in human kidney biopsies the in situ DPP4 activity and DPP4 expression were both increased in nephritic glomeruli especially within the crescents. Linagliptin could almost completely inhibit all renal DPP4 activity without any effect on DPP4 expression. Short-term treatment had no significant effect on crescent formation. However, long-term preventive treatment resulted in reduced number of crescents (51±3% vs 65±3%), glomerulosclerosis (score 1.2±0.07 vs 1.6±0.1), tubulointerstitial injury (score 1.2±0.1 vs 1.8±0.2), renal fibrosis (score 1.3±0.13 vs 1.9±0.14) and proteinuria (265±29 vs 363±22 mg/24h) compared to untreated nephritic rats. Therapeutic intervention with linagliptin resulted in weaker amelioration of renal disease at week 8, but also significantly reduced renal fibrosis (score 1.4±0.13 vs. 1.9±0.14) and crescent formation (52±4% vs. 65±3%) compared with vehicle. About 20% of all glomeruli showed Pax8+ parietal epithelial cells (PECs) on the tuft in short term treatment, being significantly reduced by therapeutic linagliptin treatment on day 14. In the long term experiment the number of Pax8+ PECs on glomerular tuft was reduced by more than 50% in both treatment groups and confirmed by quantitative mRNA analysis using isolated glomeruli. Despite the number of Pax8-positive cells on glomerular tuft was reduced by linagliptin therapy, a subpopulation of PECs positive for the transcription factor SOX9 was significantly increased on glomerular tuft compared to healthy and non-treated rats on day 14. Conclusion DPP4- inhibition with linagliptin reduced Pax8+ cells on glomerular tuft, indicating accelerated resolution of formed crescents and improvement in renal injury. This DDP4 effect might be mediated by differential regulation of a subpopulation of PECs expressing the transcription factor SOX9.