GLP signaling mediates important renal

GLP-1 signaling mediates important renal functions [101], as suggested by the expression of both DPP-4 and GLP-1R in the kidney of several species, including humans [102]. However, controversial data exists on the specific expression pattern of these proteins, based on the specificity and sensitivity of detection methods [[88], [103]]. Few studies suggest their presence in the renal blood vessels, glomerular cells and tubular cells [102]. Studies on rodents show that DPP-4 is extensively expressed on the Microcystin-LR of proximal tubules and glomerular podocytes, as well as in preglomerular vascular smooth cells and mesangial cells [[26], [104]]. Hence, DPP-4is are expected to have a significant impact on renal physiology. In addition to the direct stimulation of renal GLP-1Rs, the regulation of atrial natriuretic peptide (ANP) and the RAS represent two possible pathways underlying GLP-1 renal actions. Notably, accumulating evidence supports that incretin system is able to modulate sodium and water homeostasis [101]. The natriuretic effect is probably the best reported one in several studies, both in rodents and in humans. Chronic infusion of GLP-1 increased glomerular filtration rate (GFR), urinary flow and sodium excretion in Dahl salt-sensitive rats [[105], [106]]. However, no effect on GFR was present in rats with denervated kidneys, showing that renal GLP-1 signaling also depends on functional neurotransmission [107]. Moreover, exendin-4 increased GFR in non-diabetic mice whereas did not show acute effect in diabetic db/db mice [108]. A significant increase in urinary sodium excretion and GFR decrease have been reported in obese, insulin-resistant men [109], whereas GLP-1 infusion resulted in dose-dependent natriuretic effect without GFR change in healthy subjects [110]. The GLP-1-mediated vasodilation of glomerular capillaries increases renal blood flow and therefore GFR in healthy rodents; however, this effect is minimal in humans receiving pharmacologically relevant GLP-1 doses. On the other hand, the GLP-1-mediated decrease in the proximal tubular reabsorption increases the proximal hydrostatic pressure, thereby decreasing GFR due to a decreased glomerular pressure gradient [111]. Natriuresis has been suggested to be due to the reduction of tubular proximal reabsorption that, in turn, is predominantly mediated by the inhibition of the Na+/H+ exchanger isoform 3 (NHE3) [101]. Interestingly, GLP-1R activation has been shown to down-regulate NHE3 activity through a protein kinase A (PKA)-dependent mechanism [112]. Furthermore, it has been recently shown that GLP-1R stimulation in the heart atria can indirectly induce natriuretic and vasorelaxant effects by releasing ANP which, in turn, stimulates its own receptor in the kidney. Interestingly, in the same study, liraglutide was able to only reduce blood pressure acutely in hypertensive mouse models (e.g., angiotensin-2 induced or pressure overload) [113]. These findings highlight a gut-heart axis in mice suggesting that ANP release mediates all acute physiological GLP-1-induced renal actions. On the other hand, the existence of a functional gut-heart axis in humans is questionable: GLP-1 infusion substantially increased natriuresis but had no effect on ANP secretion in healthy males [114]. Rodent and human studies have demonstrated that GLP-1, in a GLP-1R- and PKA-dependent manner, also inhibits angiotensin-2 (ANG-2) actions by downregulating ANG-2 signaling and its plasma concentration [[113], [115], [116]]: ANG-2 is crucially involved in tubular proximal reabsorption by increasing NHE3 activity. Furthermore, GLP-1 has also been shown to decrease renal ROS production and inflammation both in vitro and in vivo by stimulating glomerular GLP-1Rs and contrasting the increase of oxidative stress induced by ANG-2 [[116], [117]]. In cultured mesangial cells, GLP-1 prevented cell damage by blocking ANG-2-induced superoxide formation, activation of NF-kB, and up-regulation of intercellular adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1: this effect was PKA-mediated [117]. Similarly, GLP-1R stimulation inhibited ANG-2 signaling via PKA-mediated cRaf phosphorylation in glomerular endothelium cells [116]. The pleiotropic properties of incretin-based therapy also include anti-inflammatory effects. In cultured mesangial cells, GLP-1 suppressed monocyte chemoattractant protein-1 (MCP-1) expression by directly stimulating GLP-1R, possibly exerting an anti-inflammatory action [118]. Furthermore, alogliptin has been reported to reduce the Toll-like receptor-4-mediated up-regulation of pro-inflammatory cytokines in mononuclear cells [67].