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Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1.
Am J Physiol Renal Physiol. 2011 Aug; 301(2):F355-63.AJ

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.

Authors+Show Affiliations

Heart Institute Medical School, Univ. of São Paulo, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21593184

Citation

Crajoinas, Renato O., et al. "Mechanisms Mediating the Diuretic and Natriuretic Actions of the Incretin Hormone Glucagon-like Peptide-1." American Journal of Physiology. Renal Physiology, vol. 301, no. 2, 2011, pp. F355-63.
Crajoinas RO, Oricchio FT, Pessoa TD, et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol. 2011;301(2):F355-63.
Crajoinas, R. O., Oricchio, F. T., Pessoa, T. D., Pacheco, B. P., Lessa, L. M., Malnic, G., & Girardi, A. C. (2011). Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. American Journal of Physiology. Renal Physiology, 301(2), F355-63. https://doi.org/10.1152/ajprenal.00729.2010
Crajoinas RO, et al. Mechanisms Mediating the Diuretic and Natriuretic Actions of the Incretin Hormone Glucagon-like Peptide-1. Am J Physiol Renal Physiol. 2011;301(2):F355-63. PubMed PMID: 21593184.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. AU - Crajoinas,Renato O, AU - Oricchio,Felipe T, AU - Pessoa,Thaissa D, AU - Pacheco,Bruna P M, AU - Lessa,Lucília M A, AU - Malnic,Gerhard, AU - Girardi,Adriana C C, Y1 - 2011/05/18/ PY - 2011/5/20/entrez PY - 2011/5/20/pubmed PY - 2011/10/4/medline SP - F355 EP - 63 JF - American journal of physiology. Renal physiology JO - Am. J. Physiol. Renal Physiol. VL - 301 IS - 2 N2 - 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. SN - 1522-1466 UR - https://www.unboundmedicine.com/medline/citation/21593184/Mechanisms_mediating_the_diuretic_and_natriuretic_actions_of_the_incretin_hormone_glucagon_like_peptide_1_ L2 - http://journals.physiology.org/doi/full/10.1152/ajprenal.00729.2010?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -