The inhibition of NPY cleavage

The inhibition of NPY cleavage may also contribute to the effect of gliptins on blood pressure [123]: NPY is an agonist of Y1 receptor mediating peripheral vasoconstriction. Interestingly, blood pressure in adult SHRs was not affected by single dose administration of a specific DPP-4i whereas blood pressure was significantly increased after DPP-4 inhibition in SHRs pre-treated with captopril. This effect was prevented by the administration of a selective Y1 receptor antagonist. On the other hand, the inhibition of DPP-4 did not affect arterial blood pressure when animals were pre-treated with a sympathetic nervous system blocker. Therefore, DPP-4 inhibition increased arterial blood pressure via Y1 receptors when elevated blood pressure had been previously reduced with anti-hypertensive drugs, provided that the sympathetic nervous system was functional. These results suggest the need to monitor the use of gliptins in hypertensive patients treated with anti-hypertensive drugs such as angiotensin converting enzyme (ACE) inhibitors [123]. Of note, DPP-4is may potentiate the ANG-2-mediated renal vasoconstriction only in SHRs [124]: this effect is mediated by the NPY/Y1 receptor pathway that promotes vasoconstriction only in these animals but not in wild-type rats [125]. Overall, the above reported preclinical evidence suggests that DDP-4is may offer renoprotective (and cardioprotective) effects in the context of hypertension and other disorders of sodium retention via both incretin-dependent and independent mechanisms. Furthermore, it is likely that long-term DDP-4 inhibition may potentially have clinical benefits in patients with diabetic chronic kidney disease (CKD), such as DN, as well as in patients with non-diabetic CKD and acute kidney injury (AKI). Accordingly, DPP-4 expression has been reported to be up-regulated in cultured human glomerular epithelial AICAR during inflammation [126] and in a rat model of type 2 diabetes mellitus (T2DM) [127]. More importantly, increased DPP-4 renal activity is considered as a biomarker for human glomerular diseases [[128], [129]].
Effects of DPP-4 inhibitors on kidney function: pathophysiological settings
Clinical evidence of renal benefits or detriments of DPP-4 inhibitors from randomized controlled clinical trials The clinical impact of DPP-4is on renal outcomes represents a timely and controversial issue, as findings from various clinical studies are somewhat conflicting. In order to catch the most relevant evidence on this topic, we approached the existing literature by using predefined search criteria (see below) in order to find the most relevant randomized controlled trials (RCTs) and meta-analyses dealing with the effects of these agents on renal outcomes in individuals with evidence of renal impairment. Main characteristics and findings from the studies retrieved (summarized in Table 2) were analyzed and discussed in a pragmatic way.
Conclusions
Conflict of interest
Introduction Plasminogen (Plg) is converted to plasmin, which is a main component of the fibrinolytic system, through the action of tissue-type plasminogen activator (tPA) or urokinase-type PA (uPA), and the inhibition of the system is achieved mainly by the plasminogen activator inhibitor-1 (PAI-1) or α2-antiplasmin (α2AP). It has been reported that fibrinolytic factors such as tPA, uPA, uPA receptor (uPAR) and PAI-1 are involved in the glucose metabolism [1], [2], [3]. However, the physiological role of main fibrinolytic component, Plg in glucose metabolism was not precisely understood. Dipeptidyl peptidase IV (DPP-4) is ubiquitously expressed in multiple cells, and cleaves numerous substrates including cytokines, neuropeptides, and the incretin hormones [4]. It has been known that the inhibition of DPP-4 elevates the levels of the incretin hormones, which regulates insulin secretion, and DPP-4 inhibitors are novel agents for the treatment of type 2 diabetes. Several studies demonstrate that DPP-4 can interact with Plg, and regulate cell invasion [5]. We herein investigated the role of Plg in the DPP-4 activity and glucose metabolism.