title: 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.
abstract: Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na(+) reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na(+) excretion, and renal membrane expression of the Na(+)/H(+) exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na(+) reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.
authors: Dept. of Medicine and Pharmacology, Division of Nephrology/Hypertension, Univ. of California San Diego and VA San Diego Healthcare System, 3350 La Jolla Village Dr. (9151 San Diego, CA 92161, USA.
authors: Timo
authors: T
authors: Rieg
authors: Maria
authors: M
authors: Gerasimova
authors: Fiona
authors: F
authors: Murray
authors: Takahiro
authors: T
authors: Masuda
authors: Tong
authors: T
authors: Tang
authors: Michael
authors: M
authors: Rose
authors: Daniel J
authors: DJ
authors: Drucker
authors: Volker
authors: V
authors: Vallon
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009318:Natriuresis / Q000187:drug effects; D045283:Natriuretic Agents / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D045283:Natriuretic Agents; D010455:Peptides; D010880:Piperidines; D018027:Receptors, Glucagon; D014688:Venoms; D014498:Uracil; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; C520853:alogliptin