Korean Diabetes J.  2008 Feb;32(1):10-20. 10.4093/kdj.2008.32.1.10.

Protective Effects of Lithospermic Acid B on Diabetic Nephropathy in OLETF Rats Comparing with Amlodipine and Losartan

• Kang ES
• Kim BS
• Kim CH
• Seo GH
• Han SJ
• Chun SW
• Hur KY
• Ahn CW
• Ha H
• Jung M
• Cha BS
• Lee HC

• KMID: 2298105
• DOI: http://doi.org/10.4093/kdj.2008.32.1.10

Abstract

BACKGROUND: Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 and type 2 diabetic animal models. We examined the effects of LAB on the prevention of diabetic nephropathy compared with amlodipine, a calcium channel blocker, and losartan, an angiotensin receptor blocker, in Otsuka Long-Evans-Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes.
METHODS
LAB (20 mg/kg), amlodipine (10 mg/kg), or losartan (10 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks.
RESULTS
None of LAB, losartan, and amlodipine exhibited effects on blood glucose levels. Treatment with amlodipine or losartan resulted in similar reductions in blood pressure; however, LAB was less effective in lowering blood pressure. Albuminuria was markedly suppressed by losartan and LAB, but not by amlodipine. LAB treatment decreased levels of renal lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta1 (TGF-beta1).
CONCLUSION
These results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing oxidative stress and inflammation as potent as losartan.

Keyword

Lithospermic acid B; Amlodipine; Losartan; OLETF rats; Diabetic nephropathy

MeSH Terms

Albuminuria
Amlodipine
Angiotensins
Animals
Benzofurans
Blood Glucose
Blood Pressure
Calcium Channels
Chemokine CCL2
Depsides
Diabetic Nephropathies
Humans
Inflammation
Lipid Peroxidation
Losartan
Male
Models, Animal
Oxidative Stress
Pyridines
Rats
Rats, Inbred OLETF
Salvia miltiorrhiza
Thiazoles
Amlodipine
Angiotensins
Benzofurans
Blood Glucose
Calcium Channels
Chemokine CCL2
Depsides
Losartan
Pyridines
Thiazoles

Figure

• 

  Fig. 1 Body weight change over time. Treatment with LAB (n = 6), losartan (n = 6), or amlodipine had no effect on the body weight gain compared with PBS treated OLETF control rats (n = 6). *P < 0.05 compared with LETO (n = 6).

• 

  Fig. 2 Profiles of systolic blood pressure change. OLETF rats progressively developed hypertension, whereas treatment with either losartan (n = 6), amlodipine (n = 6), or LAB (n = 6) reduced systolic blood pressure significantly. Treatment with losartan and amlodipine resulted in similar reductions in SBP, while treatment with LAB had a less potent effect on lowering blood pressure. *P < 0.05 compared with LETO (n = 6), †P < 0.05 compared with PBS treated OLETF (n = 6). a and b represent P < 0.05.

• 

  Fig. 3 A. Renin mRNA expression profile. B. Angiotensinogen mRNA expression profile. At 38 weeks of age, OLETF rat showed higher renal renin and angiotensinogen mRNA levels than LETO rats. Treatment with losartan (n = 6) significantly increased renin mRNA levels but had no effect on angiotensinogen mRNA levels in OLETF rats. Treatment with amlodipine (n = 6) or LAB (n = 6) had no significant effects on renin and angiotensinogen mRNA expression level in OLETF rats. Values are means ± SE. *P < 0.05 compared with LETO (n = 6), †P < 0.05 compared with PBS treated OLETF (n = 6).

• 

  Fig. 4 Profile of renal MCP-1 levels by relative PCR. MCP-1 level in creased in OLETF rats compared with LETO rats. Only treatment with LAB caused a decrease in renal cortical MCP-1 mRNA expression levels. LAB decreased amount of MCP-1 expression to the 57% level of PBS treated OLETF control (n = 6).

• 

  Fig. 5 Profiles of glucose tolerance test at 38 weeks. Blood glucose levels were the greatest 30 min after the intraperitoneal glucose injection in all animals, which was followed by a distinct disposal phase. There was a delay in blood glucose disposal in OLETF rats. Treatment with LAB (n = 6), losartan (n = 6), or amlodipine (n = 6) did not significantly influence fasting and postprandial plasma glucose levels. *P < 0.05 compared with LETO (n = 6).

• 

  Fig. 6 Effects on albuminuria. The amount of albuminuria was markedly suppressed by treatment with losartan (n = 6) and LAB (n = 6), but not with amlodipine (n = 6). Values are means ± SE. *P < 0.05 compared with LETO (n = 6), †P < 0.05 compared with OLETF (n = 6).

• 

  Fig. 7 ELISA results for TGF-β1 protein expression in the kidney cortex. Quantitative analyses of TGF-β1 showed that losartan (n = 6) and LAB (n = 6) strongly inhibited TGF-β1 protein expression in the renal cortex of OLETF rats. Values are means ± SE. *P < 0.05 compared with LETO (n = 6), †P < 0.05 compared with PBS treated OLETF (n = 6).

• 

  Fig. 8 Effect of treatments on renal cortex MDA levels. OLETF rats showed higher levels of renal cortical MDA contents compared with LETO rats. Treatment with amlodipine (n = 6), losartan (n = 6) or LAB (n = 6) decreased the renal cortical MDA concentration. Values are means ± SE. *P < 0.05 compared with LETO (n = 6), †P < 0.05 compared with PBS treated OLETF (n = 6). a and b represent P < 0.05.

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