title: Intestinal regulation of urinary sodium excretion and the pathophysiology of diabetic kidney disease: a focus on glucagon-like peptide 1 and dipeptidyl peptidase 4.
abstract: The tubular hypothesis of glomerular filtration and nephropathy in diabetes is a pathophysiological concept that assigns a critical role to the tubular system, including proximal tubular hyper-reabsorption and growth, which is relevant for early glomerular hyperfiltration and later chronic kidney disease. Here we focus on how harnessing the bioactivity of hormones released from the gut may ameliorate the early effects of diabetes on the kidney in part by attenuating proximal tubular hyper-reabsorption and growth. The endogenous tone of the glucagon-like peptide 1 (GLP-1)/GLP-1 receptor (GLP-1R) system and its pharmacological activation are nephroprotective in diabetes independent of changes in blood glucose. This is associated with suppression of increases in kidney weight and glomerular hyperfiltration, which may reflect, at least in part, its inhibitory effects on tubular hyper-reabsorption and growth. Inhibition of dipeptidyl peptidase 4 (DPP-4) is also nephroprotective independent of changes in blood glucose and involves GLP-1/GLP-1R-dependent and -independent mechanisms. The GLP-1R agonist exendin-4 induces natriuresis via activation of the GLP-1R. In contrast, DPP4 inhibition increases circulating GLP-1, but drives a GLP-1R-independent natriuretic response, implying a role for other DPP-4 substrates. The extent to which the intrarenal DPP-4/GLP-1 receptor system contributes to all these changes remains to be established, as does the direct impact of the system on renal inflammation.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA Department of Pharmacology, University of California San Diego, La Jolla, CA, USA Department of Veterans Affairs, San Diego Healthcare System, San Diego, CA, USA vvallon@ucsd.edu.
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Docherty
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology / Q000652:urine; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D005919:Glomerular Filtration Rate; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009318:Natriuresis / Q000187:drug effects; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D065667:Renal Elimination; D015398:Signal Transduction; D012964:Sodium / Q000652:urine*
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D012964:Sodium; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
references.citation: J Biol Chem. 2001 Dec 7;276(49):46671-7
references.pmid: 11590171
references.citation: Horm Metab Res. 2014 Sep;46(10):717-21
references.pmid: 24710699
references.citation: Am J Physiol Cell Physiol. 2004 Nov;287(5):C1238-45
references.pmid: 15213057
references.citation: Kidney Int. 2014 Mar;85(3):579-89
references.pmid: 24152968
references.citation: Biochem J. 1976 Jul 1;157(1):169-82
references.pmid: 962853
references.citation: Arch Biochem Biophys. 2008 Oct 15;478(2):136-42
references.pmid: 18708025
references.citation: PLoS One. 2014 Apr 22;9(4):e93447
references.pmid: 24755682
references.citation: Digestion. 2006;73(2-3):142-50
references.pmid: 16809911
references.citation: Lancet. 2006 Nov 11;368(9548):1696-705
references.pmid: 17098089
references.citation: Nat Med. 2013 May;19(5):567-75
references.pmid: 23542788
references.citation: Regul Pept. 2007 Jun 7;141(1-3):120-8
references.pmid: 17276524
references.citation: Endocr Connect. 2014 Jan 21;3(1):11-6
references.pmid: 24327600
references.citation: Annu Rev Physiol. 2012;74:351-75
references.pmid: 22335797
references.citation: Am J Physiol Renal Physiol. 2014 Jan;306(2):F194-204
references.pmid: 24226524
references.citation: J Am Soc Nephrol. 2013 Dec;24(12):2034-43
references.pmid: 24092928
references.citation: Am J Physiol Renal Physiol. 2011 Aug;301(2):F355-63
references.pmid: 21593184
references.citation: Eur J Pharmacol. 2002 Jan 11;434(3):163-7
references.pmid: 11779579
references.citation: Diabetologia. 2011 Apr;54(4):965-78
references.pmid: 21253697
references.citation: Am J Kidney Dis. 2009 Jan;53(1 Suppl):S1-374
references.pmid: 19111206
references.citation: Am J Physiol Renal Physiol. 2013 Jan 15;304(2):F137-44
references.pmid: 23019232
references.citation: Pharmacol Ther. 2004 Nov;104(2):137-62
references.pmid: 15518884
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1009-22
references.pmid: 21228342
references.citation: Biochem Biophys Res Commun. 2014 Jan 17;443(3):828-33
references.pmid: 24342619
references.citation: Annu Rev Physiol. 2008;70:379-403
references.pmid: 17988205
references.citation: Am J Physiol Renal Physiol. 2008 Feb;294(2):F414-22
references.pmid: 18077600
references.citation: Am J Physiol Renal Physiol. 2012 Oct;303(7):F963-71
references.pmid: 22832924
references.citation: Am J Physiol Renal Physiol. 2013 Jan 15;304(2):F156-67
references.pmid: 23152292
references.citation: J Clin Endocrinol Metab. 2004 Jun;89(6):3055-61
references.pmid: 15181098
references.citation: J Am Soc Nephrol. 2002 Jul;13(7):1865-71
references.pmid: 12089382