Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1

Abstract

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered a promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in a glucose-dependent manner. Cumulative evidence supports a role for GLP-1 in modulating renal function; however, the mechanisms by which GLP-1 induces diuresis and natriuresis have not been completely established. This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 μg·kg(-1)·min(-1)) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na(+)/H(+) exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism. Reduced proximal tubular bicarbonate flux rate was associated with a significant increase of NHE3 phosphorylation at the PKA consensus sites in microvillus membrane vesicles. Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and by downregulation of NHE3 activity in the renal proximal tubule. Moreover, our findings support the view that GLP-1-based agents may have a potential therapeutic use not only as antidiabetic drugs but also in hypertension and other disorders of sodium retention.

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

“…The DPP-4 inhibitors Lys [Z(NO 2 )]-pyrrolidide and P32/98 inhibited NHE3-mediated Na ϩ reabsorption in rat renal proximal tubule in vivo (6,16). Studies in an opossum kidney proximal tubule cell line indicate that the enzymatic activity of DPP-4 in the proximal tubular brush border may locally affect the generation or breakdown of endogenous factors that regulate Na ϩ reabsorption via effects on NHE3 activity (17).…”

“…Analysis of GLP-1R expression in rats (6), pigs, and humans (34) localized the GLP-1R to the brush border microvilli of proximal tubules. Intravenous infusion of GLP-1 increased glomerular filtration rate (GFR), inhibited proximal tubular reabsorption, and increased urine flow and Na ϩ excretion in rats (6,30). In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in urinary Na ϩ excretion without changing GFR (20,21).…”

“…In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in urinary Na ϩ excretion without changing GFR (20,21). Studies in intact rat and porcine renal proximal tubules indicated that GLP-1 decreases Na ϩ /H ϩ exchanger (NHE3)-mediated bicarbonate reabsorption (6,34). Moreover, GLP-1 increased expression of NHE3 phosphorylated at S552 and S605, two PKA consensus sites, without changing total NHE3 expression, in rat proximal tubular brush border microvilli (6).…”

Gut hormones and gut microbiota: implications for kidney function and hypertension

“…Once released, this incretin hormone stimulates insulin secretion, suppresses glucagon release, decelerates gastric emptying, improves insulin sensibility, and reduces food intake. 9,10 Glp-1 is rapidly degraded by the dipeptidyl peptidase-4 inhibitor (DPP-4), which circulates in the plasma and limits the half-life of Glp-1 to w2 minutes. 11 Cumulative evidence supports a role for GLP-1 in modulation of renal function and regulation of BP.…”

“…Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and downregulation of NHE3 activity in the renal proximal tubule. 9 Liraglutide and DPP-4 inhibitors which enhance GLP-1 activity have been shown to lower blood pressure in animal models of obesity and hypertension and in humans with T2DM. 17,18 In addition, glucocorticoids and aldosterone play a role in regulation of sodium absorption in the gastrointestinal tract.…”