Diabetes Metab J.  2012 Apr;36(2):128-135. 10.4093/dmj.2012.36.2.128.

Effect of Eplerenone, a Selective Aldosterone Blocker, on the Development of Diabetic Nephropathy in Type 2 Diabetic Rats

• Ahn JH
• Hong HC
• Cho MJ
• Kim YJ
• Choi HY
• Eun CR
• Yang SJ
• Yoo HJ
• Kim HY
• Seo JA
• Kim SG
• Choi KM
• Baik SH
• Choi DS
• Kim NH

• KMID: 2281415
• DOI: http://doi.org/10.4093/dmj.2012.36.2.128

Abstract

BACKGROUND
Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats.
METHODS
Animals were divided into six groups as follows: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks.
RESULTS
Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor-1, transforming growth factor-beta1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups.
CONCLUSION
Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug.

Keyword

Aldosterone receptor blocker; Diabetic nephropathy; Eplerenone; Lisinopril; Type 2 diabetic rats

MeSH Terms

Aldosterone
Animals
Collagen Type IV
Connective Tissue Growth Factor
Diabetic Nephropathies
Fibronectins
Lisinopril
Mineralocorticoid Receptor Antagonists
Peptidyl-Dipeptidase A
Plasminogen Activators
Rats
Rats, Inbred OLETF
Receptors, Mineralocorticoid
Renin-Angiotensin System
RNA, Messenger
Spironolactone
Aldosterone
Collagen Type IV
Connective Tissue Growth Factor
Fibronectins
Lisinopril
Mineralocorticoid Receptor Antagonists
Peptidyl-Dipeptidase A
Plasminogen Activators
RNA, Messenger
Receptors, Mineralocorticoid
Spironolactone

Figure

• 

  Fig. 1 Effect of eplerenone and lisinopril on urinary albumin excretion. Twenty-four hour urinary albumin excretion was corrected by urine creatinine concentration. Values are presented as mean±standard deviation. OLETF, Otsuka Long-Evans Tokushima Fatty (OLETF) rat control; OE50, OLETF rats treated with eplerenone at 50 mg/kg/day; OE200, OLETF rats treated with eplerenone at 200 mg/kg/day; OA, OLETF rats treated with lisinopril at 10 mg/kg/day; OAE, OLETF rats treated with lisinopril at 10 mg/kg/day and eplerenone at 200 mg/kg/day; LETO, non-diabetic control. aP<0.05 vs. OLETF, bP<0.05 vs. OE50, cP<0.05 vs. OE200, dP<0.05 vs. OA.

• 

  Fig. 2 Renal histologic findings and glomerulosclerosis index according to the treatment groups. (A) Renal histologic findings (periodic acid-Schiff [PAS] staining). (B) Glomerulosclerosis index according to the study groups on a logarithmic scale. PAS staining of glomeruli showed marked glomerulosclerosis in the OLETF group compared to treatment groups (×200). Glomerulosclerosis indices are presented as mean±standard deviation. Statistical analysis was done after logarithmic transformation. OLETF, Otsuka Long-Evans Tokushima Fatty (OLETF) rat control; OE50, OLETF rats treated with eplerenone at 50 mg/kg/day; OE200, OLETF rats treated with eplerenone at 200 mg/kg/day; OA, OLETF rats treated with lisinopril at 10 mg/kg/day; OAE, OLETF rats treated with lisinopril at 10 mg/kg/day and eplerenone at 200 mg/kg/day; LETO, non-diabetic control. aP<0.05, vs. OLETF.

• 

  Fig. 3 mRNA expression of pro-fibrotic and pro-inflammatory cytokines in renal cortical tissues in experimental animals. mRNA expression of (A) type I collagen, (B) type IV collagen, (C) plasminogen activator inhibitor-1 (PAI-1), (D) transforming growth factor-β (TGF-β), (E) connective tissue growth factor (CTGF), and (F) fibronectin are presented relatively compared to β-actin mRNA expression. Values are presented as mean±standard deviation. Statistical analysis was done after logarithmic transformation. OLETF, Otsuka Long-Evans Tokushima Fatty (OLETF) rat control; OE50, OLETF rats treated with eplerenone at 50 mg/kg/day; OE200, OLETF rats treated with eplerenone at 200 mg/kg/day; OA, OLETF rats treated with lisinopril at 10 mg/kg/day; OAE, OLETF rats treated with lisinopril at 10 mg/kg/day and eplerenone at 200 mg/kg/day; LETO, non-diabetic control. aP<0.05, vs. OLETF, bP<0.05, vs. OA.

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