dihydrofolate reductase Based on the above background
Based on the above background, gliptins may exert natriuretic and diuretic effects as well [, ]. In accordance with this, Girardi and co-workers have demonstrated a physical interplay between DPP-4 and the NHE3 exchanger in the brush-border epithelium of the proximal renal tubule, suggesting a functional relationship between them [, , ]. This supports the involvement of DPP-4 enzyme in the NHE3-mediated dihydrofolate reductase of sodium, bicarbonate and water. DPP-4 inhibition might enhance natriuresis and diuresis in two ways: 1) by promoting down-regulation of NHE3 activity associated with GLP-1R activation and 2) by directly impairing NHE3 function due to the inhibition of DPP-4. The latter pathway is supported by in vitro as well as in vivo studies by Girardi et al. [, ] clearly demonstrating a correlation between DPP-4 inhibition and decreased NHE3 function. Specifically, DPP-4 inhibition has been reported to decrease NHE3 function in a cultured opossum kidney proximal tubular cell line  and in normotensive wild-type Wistar rats . In the latter study, DPP-4 inhibition resulted in a diuretic and natriuretic effect, which was associated with the redistribution of NHE3 and a small fraction of DPP-4 from the apical microvillar membranes to the intermicrovillar microdomain of the brush border. In opossum kidney proximal cells, suppression of NHE3 activity by DPP-4is was not antagonized by a PKA inhibitor . This pre-clinical evidence suggests that the natriuretic and anti-hypertensive effects of gliptins may rely on mechanisms other than renal GLP-1 signaling. However, the inhibition of NHE3 function by exendin-4 (a GLP-1R agonist)  supports the first hypothesized pathway, which is the enhancement of GLP-1 physiological action on its own receptors (related to NHE3) through the reduction of GLP-1 degradation. Nevertheless, the possible co-existence of both pathways cannot be ruled-out. Overall, these mechanisms further clarify the aforementioned studies showing the sitagliptin-mediated blood pressure attenuation in spontaneously hypertensive rats (SHRs) and hypertensive diabetic patients [, ]. In line with the above results by Girardi and colleagues , Rieg et al.  have demonstrated that alogliptin induced natriuretic and diuretic effects in non-diabetic mice independently of GLP-1R or changes in NHE3. Accordingly, in contrast to exendin-4, the alogliptin-induced diuresis and natriuresis were preserved in GLP-1R knockout mice. On the other hand, in contrast to exendin-4, the GLP-1R-independent natriuretic effect of alogliptin was abolished in a mouse model of obese type 2 diabetes, where the GLP-1R-mediated natriuretic mechanisms were clearly kept. Furthermore, DPP-4 inhibition did not increase GFR in healthy rats, while both GLP-1 and exendin-4 markedly increased creatinine clearance . These findings indicate that, under physiological conditions, the mechanisms mediating the diuretic and natriuretic actions of DPP-4is diverge from both GLP-1 and GLP-1RAs. In this regard, it should be considered that multiple peptide substrates other than GLP-1 are likely cleaved by DPP-4 [, ], thus suggesting that DPP-4 inhibition may affect the kidney physiology by other, non-incretin mediated pathways. For example, DPP-4 may target ANP, brain-derived natriuretic peptide (BNP), neuropeptide Y (NPY), peptide YY (PYY), and stromal cell-derived factor (SDF)-1α . Similar to ANP, BNP is known for its natriuretic and vasorelaxant effects. NPY promotes vasoconstriction and up-regulation of sympathetic nerve activity whereas PYY mediates vasoconstriction only. SDF-1α plays a crucial role in the protection of ischemically-injured tissues as well as in angiogenesis. DDP-4is may therefore participate in the modulation of natriuresis, blood pressure, vascular function, and tissue repair by augmenting endogenous levels of these peptides [, ].