Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose.


METHODS
We administered exendin-4 at 10 μg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro.


RESULTS
Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-κB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells.


CONCLUSIONS
These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
R
R
Kodera
K
K
Shikata
H U
HU
Kataoka
T
T
Takatsuka
S
S
Miyamoto
M
M
Sasaki
N
N
Kajitani
S
S
Nishishita
K
K
Sarai
D
D
Hirota
C
C
Sato
D
D
Ogawa
H
H
Makino
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000517:prevention & control; D000077270:Exenatide; D005455:Fluorescent Antibody Technique; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use*
D001786:Blood Glucose; D024141:Collagen Type IV; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D016328:NF-kappa B; D010455:Peptides; D018027:Receptors, Glucagon; D014409:Tumor Necrosis Factor-alpha; D014688:Venoms; D018799:Intercellular Adhesion Molecule-1; D000077270:Exenatide
Diabetologia. 2009 Apr;52(4):691-7
19198800
Diabetes Care. 2005 Dec;28(12):2890-5
16306550
Nephrol Dial Transplant. 2003 Feb;18(2):265-72
12543879
Gastroenterology. 2007 May;132(6):2131-57
17498508
N Engl J Med. 1988 May 19;318(20):1315-21
3283558
FASEB J. 1997 Sep;11(11):851-7
9285483
J Clin Invest. 1994 Feb;93(2):536-42
8113392
Diabetologia. 2003 Oct;46(10):1428-37
13680125
Diabetes. 2003 Oct;52(10):2586-93
14514644
Regul Pept. 2007 Jun 7;141(1-3):120-8
17276524
J Am Soc Nephrol. 1997 Oct;8(10):1525-36
9335380
J Am Soc Nephrol. 2007 Apr;18(4):1227-38
17360951
Diabetes. 1991 Apr;40(4):405-12
2010041
J Leukoc Biol. 1999 Dec;66(6):876-88
10614768
Eur Heart J. 2005 Jan;26(1):11-7
15615794
Endocrinology. 1996 Jul;137(7):2968-78
8770921
N Engl J Med. 2004 Sep 23;351(13):1296-305
15385656
J Biol Chem. 2005 Nov 25;280(47):39616-26
16135519
Am J Kidney Dis. 1993 May;21(5):480-5
8488815
Nephrol Dial Transplant. 2005 Nov;20(11):2420-6
16115854
Diabetologia. 2003 Oct;46(10):1402-7
12928771
J Clin Invest. 2003 Dec;112(12):1821-30
14679177
Diabetologia. 2005 Nov;48(11):2402-11
16231067
N Engl J Med. 1999 Jan 14;340(2):115-26
9887164
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8015-20
10859350
Antioxid Redox Signal. 2009 Apr;11(4):791-810
18783313
J Biol Chem. 1996 Aug 23;271(34):20828-35
8702838
Nature. 1996 Jan 4;379(6560):69-72
8538742
Diabetologia. 1998 Feb;41(2):185-92
9498652
Kidney Int. 2001 Feb;59(2):415-24
11168923
Am J Physiol Renal Physiol. 2007 Apr;292(4):F1141-50
17190910
J Biol Chem. 2007 Nov 30;282(48):34787-800
17913709
J Lab Clin Med. 1968 Jun;71(6):1034-9
5654774
J Endocrinol. 2009 Apr;201(1):59-66
19136619
Am J Physiol. 1997 Nov;273(5):E981-8
9374685
Diabetes. 1993 May;42(5):658-61
8482423
Endocrinology. 2002 Nov;143(11):4397-408
12399437
Pharmacol Ther. 2007 Mar;113(3):546-93
17306374
J Am Soc Nephrol. 2005 Nov;16(11):3326-38
16177002
J Clin Invest. 2008 May;118(5):1645-56
18431508
Proc Natl Acad Sci U S A. 1989 Dec;86(24):9697-701
2602371
J Clin Invest. 1997 Jul 1;100(1):115-26
9202063
Diabetes. 1997 Dec;46(12):2075-81
9392499
Diabetes. 2010 Apr;59(4):1030-7
20068138
J Am Soc Nephrol. 2006 Aug;17(8):2100-5
16825327
Biochem Biophys Res Commun. 2009 Feb 27;380(1):44-9
19150338
Diabetes. 1995 Oct;44(10):1139-46
7556948
J Clin Endocrinol Metab. 2004 Jun;89(6):3055-61
15181098