Combined Therapy of Rhein and Benazepril on the Treatment of Diabetic Nephropathy in db/db Mice

 

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Abstract

Objective: Rhein and angiotensin-converting enzyme inhibitor (ACEI) have been reported to prevent the progression of diabeic nephropahthy (DN). We futher explore the unknown ability to induce renal-protection of rhein and ACEI combined therapy in DN compared with the therapeutic effects of single treatment of them by using db/db mouse of type 2 diabetes model.

Methods: db/db and db/m mice, 8 weeks of age, were divided into five groups according to the following treatments: (A) db/m, given saline treatment; (B) db/db, given saline treatment; C db/db, given rhein treatment (150 mg/kg/day); (D) db/db, given benazepril treatment (10 mg/kg/day); (E) db/db, given rhein (150 mg/kg/day) with benazepril (10 mg/kg/day). Body weight, plasma glucose, plasma lipid and 24 h urinary albumin excretion levels were measured every 4 weeks. Morphometry of renal tissue and immunohistology of transforming growth factor-β1 (TGF-β) and fibronectin were determined for all groups at the end of the treatment.

Results: It was found that after treatment urinary albumin excretion was reduced after 4 weeks treatment in group E and after 8 weeks treatment in groups C and D, when compared to group B (p<0.05). Plasma creatinine levels dropped significantly for group E, compared with the diabetic control group by the end of the treatment period. Futhermore, after the treatment body weight, plasma glucose, cholesterol, triglyceride and low density lipoprotein all decreased in groups C and E compared to group B (p<0.05). Histological morphometric analysis revealed that the whole glomerular area and extracellular matrix area was significantly reduced in groups C, D and E compared to group B, at 20 weeks of age, an effect most pronounced in group E. Using immunohistochemistry, the expression of fibronectin and TGF-β1 in groups C, D and E was found to have decreased compared to group B, after 12 weeks treatment, again the effect being more pronounced in group E.

Conclusions: There appeared to be a similar renal protective effect of rhein compared with benazepril in diabetic nephropathy. A combined therapy may offer a more beneficial complementary effect on kidney injury in db/db mice, as reflected by urinary albumin excretion, renal function and histological changes. Our findings suggest that a therapeutic approach that combines rhein with ACEI provides a more effective therapy for DN than does either agent alone.

References

• 1 Leon CA, Raij L. Interaction of haemodynamic and metabolic pathways in the genesis of diabetic nephropathy.  J Hypertens. 2005;  23 1931-7
  PubMedGoogle Scholar
• 2 Benigni A, Zoja C, Corna D. et al . Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat.  J Am Soc Nephrol. 2003;  14 1816-24
  CrossrefPubMedGoogle Scholar
• 3 Zoja C, Corna D, Camozzi D. et al . How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach.  J Am Soc Nephrol. 2002;  13 2898-908
  CrossrefPubMedGoogle Scholar
• 4 Raimondi L, Banchelli Soldaini G, Buffoni F. et al . Rhein and derivatives. In vitro studies on their capacity to inhibit certain proteases.  Pharmacol Res Commun. 1982;  14 103-112
  CrossrefPubMedGoogle Scholar
• 5 Kean EA, Gutman M, Singer TP. Rhein, a selective inhibitor of the DPNH-flavin step in mitochondrial electron transport.  Biochem Biophys Res Commun.. 1970;  40 1507-1513
  PubMedGoogle Scholar
• 6 Kiritoshi S, Nishikawa T, Sonoda K. et al . Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy.  Diabetes. 2003;  52 2570-7
  CrossrefPubMedGoogle Scholar
• 7 Dai CS, Liu ZH, Chen HP. Effects of rhein on inhibiting the progression of diabetic nephropathy in STZ-induced diabetic rats.  J Nephrol Dial Transplant. 1998;  8 413-505
  PubMedGoogle Scholar
• 8 Zhu JM, Liu ZH, Huang YF. Therapeutic effect of rhein on diabetic nephropathy in db/db mice.  J Nephrol Dial Transplant. 2002;  11 3-10
  PubMedGoogle Scholar
• 9 Guo XH, Liu ZH, Peng A. Rhein restards the progression of type 2 diabetic nephropathy.  Chin J Nephrol. 2002;  18 280-284
  PubMedGoogle Scholar
• 10 Liu ZH, Li YJ, Chen ZH, Liu D, Li LS. Glucose transporter in human glomerular mesangial cells modulated by transforming growth factor-beta and rhein.  Acta Pharmacol Sin. 2001;  22 169-75
  PubMedGoogle Scholar
• 11 Zhu J, Liu Z, Huang H, Chen Z, Li L. Rhein inhibits transforming growth factor beta1 induced plasminogen activator inhibitor-1 in endothelial cells.  Chin Med J (Eng). 2003;  116 354-9
  PubMedGoogle Scholar
• 12 Zhang J, Liu Z, Chen Z, Li Y, Li L. Effect of rhein on glucose transporter-1 expression and its function in glomerular mesangial cells.  Chin Med J (Engl). 1999;  112 1077-1079
  PubMedGoogle Scholar
• 13 O’Connor AS, Schelling JR. Diabetes and the kidney.  Am J Kindney Dis. 2005;  46 766-73
  PubMedGoogle Scholar
• 14 Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy.  J Am Soc Nephrol. 2005;  16 ((Suppl 1)) S30-3
  CrossrefPubMedGoogle Scholar
• 15 Tamura J, Konno A, Hashimoto Y, Kon Y. Upregulation of renal renin-angiotensin system in mouse diabetic nephropathy.  Jpn J Res. 2005;  53 13-26
  PubMedGoogle Scholar
• 16 UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet. 1998;  352 837-853
  CrossrefPubMedGoogle Scholar
• 17 Andersen S, Blouch K, Bialek J, Deckert M, Parving HH, Myers BD. Glomerular permselectivity in early stages of overt diabetic nephropathy.  Kidney Int. 2000;  58 2129-2137
  CrossrefPubMedGoogle Scholar
• 18 Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis.  Kidney Int. 2001;  59 260-269
  CrossrefPubMedGoogle Scholar
• 19 Cooper ME, Jandeleit-Dahm KA. Lipids and diabetic renal disease.  Curr Diab Rep. 2005;  5 445-8
  CrossrefPubMedGoogle Scholar
• 20 S’Vaquero M, Pastor C, Galimany R, Romero R. Fosinopril ameliorates exogenous cholesterol-induced incipient glomerular lesions in obese Zucker rats. Effects on eicosanoid secretion.  Nephrol Dial Transplant. 1998;  13 2227-33
  PubMedGoogle Scholar
• 21 Fuad N, Ziyadeh Brenda B, Hoffman Dong, Cheol Han M. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice.  PNAS. 2000;  14 8015-8020
  PubMedGoogle Scholar
• 22 Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S, Sugimoto T, Yasuda H, Kashiwagi A, Ways DK, King GL, Kikkawa R. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes.  FASEB J. 2000;  14 439-447
  PubMedGoogle Scholar
• 23 Guo XH, Liu ZH, Dai CS, Li H, Liu D, Li LS. Rhein inhibits cell hypertrophy and accumulation of extracellular matrix in renal tubular epithelial cells inducedby transforming growth factor β1.  Acta Pharmacol Sin. 2001;  22 934-938
  PubMedGoogle Scholar
• 24 Brownlee M. A radical explanation for glucose-induced beta cell dysfunction.  J Clin Invest. 2003;  112 1788-90
  CrossrefPubMedGoogle Scholar
• 25 Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials.  Diabetes Metab. 2004;  30 487-96
  PubMedGoogle Scholar
• 26 Luno J, Praga M, de Vinuesa SG. The reno-protective effect of the dual blockade of the rennin angiotensin system.  Curr Pharm Des.. 2005;  11 1291-1300
  CrossrefPubMedGoogle Scholar
• 27 Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study.  BMJ. 2000;  321 1440-1444
  CrossrefPubMedGoogle Scholar

Correspondence

Z. LiuMD 

Research Institute of Nephrology

Jinling Hospital

Nanjing University School of Medicine

Nanjing 210002

China

Email: zhihong_rin@yahoo.com

Email: jzhttff@yahoo.com.cn