Sitagliptin Prevents Inflammation and Apoptotic Cell Death in the Kidney of Type 2 Diabetic Animals

Abstract

This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of type 2 diabetes mellitus; the Zucker diabetic fatty (ZDF) rat: 20-week-old rats were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia and blood HbA1c levels were monitored, as well as kidney function and lesions. Kidney mRNA and/or protein content/distribution of DPP-IV, GLP-1, GLP-1R, TNF-α, IL-1β, BAX, Bcl-2, and Bid were evaluated by RT-PCR and/or western blotting/immunohistochemistry. Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia and HbA1c (by about 22.5% and 1.2%, resp.) and ameliorated tubulointerstitial and glomerular lesions. Sitagliptin prevented the diabetes-induced increase in DPP-IV levels and the decrease in GLP-1 levels in kidney. Sitagliptin increased colocalization of GLP-1 and GLP-1R in the diabetic kidney. Sitagliptin also decreased IL-1β and TNF-α levels, as well as, prevented the increase of BAX/Bcl-2 ratio, Bid protein levels, and TUNEL-positive cells which indicates protective effects against inflammation and proapoptotic state in the kidney of diabetic rats, respectively. In conclusion, sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and antiapoptotic properties.

Inhibition of dipeptidyl peptidase IV protects tacrolimus-induced kidney injury

“…Many studies have demonstrated that DPP IV inhibitors inhibit the production of inflammatory cytokines and the activation of the nuclear factor-κB, suggesting that it has an anti-inflammatory effect. 10,12,24 Consistent with this, the current in vivo results showed that the administration of MK0626 reduced the number of positive cells and the immunoreactivity of ED-1 in the injured area, as well as the levels of OPN, as shown in Figure 1. These findings suggest that MK0626 exerts an antiinflammatory effect via the inhibition of macrophage migration to the injured area, thus resulting in a reduction in the production of proinflammatory cytokines.…”

The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial

“…GLP-1 has been reported to have various renoprotective effects [21][22][23][24][25][26][27][28][29][30][31], but renal expression of GLP-1 is suppressed in T2DM [32]. Sitagliptin elevates downregulated intrarenal GLP-1 expression in the T2DM rat model [32]. In addition, DPP-4 has been elucidated to degrade many peptides such as glucagon-like peptide-2 (GLP-2), BNP, ANP, stromal cell-derived factor (SDF)-1α, substance P, neuropeptide Y, peptide YY, and so on.…”

“…Furthermore, DPP-4 inhibitors may enhance the secretion of BNP or ANP from the atrium, resulting in natriuresis [37]. In T2DM animal models such as Zucker diabetic fatty rats [32], sitagliptin has been reported to suppress the inflammatory cytokines and apoptosis, resulting in an improvement of glomerular and tubular atrophies. Furthermore, in streptozotocin-induced diabetic rats, linagliptin suppressed enhanced DPP-4 activity and ameliorated kidney fibrosis [38].…”

Incretin-based therapy: renal effects

“…У крыс линии ZDF (модель ожирения и СД2), получавших в течение 6 недель ситаглиптин, в сравнении с группой плацебо на фоне улучшения по-казателей гликемии и липидного обмена зафиксиро-ван меньший уровень мочевины в крови и малонового диальдегида в тканях почек, снижение проявлений гло-мерулосклероза, гломерулярной атрофии и гиалиноза сосудистого полюса клубочка, уменьшение степени ин-терстициального фиброза, тубулярной атрофии и гиа-линоза артериол [39]. Торможение развития атрофии клубочков и интерстициального фиброза на фоне си-таглиптина в данной модели ДН сопровождалось сни-жением синтеза TNFα, IL-1β и торможением апоптоза клеток почек [40].…”