Abstract
Treatment with angiotensin II type 1 receptor blockers (ARBs) is the first-line therapy for hypertensive patients with diabetic nephropathy. However, emerging clinical evidence indicates that mineralocorticoid receptor (MR) blockers have blood pressure-independent antiproteinuric effects. We sought to determine whether treatment with an MR blocker, eplerenone, enhances the effects of an ARB, telmisartan, on podocyte injury and proteinuria in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats. From 20 to 50 weeks old, diabetic OLETF rats showed higher systolic blood pressure (SBP) and urinary protein excretion (UproteinV) than nondiabetic control Long-Evans-Tokushima-Otsuka rats. At 50 weeks old, OLETF rats also showed glomerular sclerosis and podocyte injury, whereas nephrin and podocin mRNA levels in isolated glomeruli were significantly decreased. Treatment with telmisartan (3 mg/kg/day p.o.) decreased SBP and UproteinV, increased nephrin and podocin mRNA levels, and attenuated glomerular sclerosis and podocyte injury. Eplerenone (100 mg/kg/day p.o.) did not alter SBP but elicited similar changes in renal parameters. However, greater reductions in UproteinV and podocyte injury and greater increases in nephrin and podocin mRNA levels were observed in the combination treatment group. Hydralazine (25 mg/kg/day p.o.) decreased SBP but did not alter any renal parameters. These data indicate that MR blockade enhances the SBP-independent antiproteinuric effect of an ARB through inhibiting podocyte injury in type 2 diabetic rats.
Footnotes
This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant-in-Aid for Scientific Research 20590253]; the Kagawa University Project Research Fund 2009 (to A.N.); the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK072408] (to H.K.); and the Medical Research Fund from Osaka City General Hospital (to Y.K. and M.I.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.158113.
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ABBREVIATIONS:
- ACEI
- angiotensin-converting enzyme inhibitor
- AngII
- angiotensin II
- ARB
- angiotensin II type 1 receptor blocker
- MR
- mineralocorticoid receptor
- OLETF
- Otsuka-Long-Evans-Tokushima-Fatty
- LETO
- Long-Evans-Tokushima-Otsuka
- PPBG
- postprandial blood glucose
- UproteinV
- urinary protein excretion rate
- SBP
- systolic blood pressure
- PAS
- periodic acid-Schiff
- Sgk
- serum glucocorticoid-dependent kinase
- SMA
- smooth muscle actin
- Cr
- creatinine
- CKD
- chronic kidney disease.
- Received June 26, 2009.
- Accepted November 24, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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