Long-term treatment of sirolimus but not cyclosporine ameliorates diabetic nephropathy in the rat.
BACKGROUND
Not just de novo induction of diabetes mellitus, but also the progression of diabetic nephropathy may be enhanced under immunosuppressive therapy after organ transplantation. We evaluated whether sirolimus (SRL) or cyclosporine A (CsA) therapy would be a superior immunosuppressant in streptozotocin-induced diabetic nephropathy.


METHODS
Diabetes was induced by intravenous injection of streptozotozin (60 mg/kg body weight) in 26 male Sprague-Dawley rats. Eight days after diabetes induction, animals were divided into three groups, which were treated with placebo (n=8), SRL (n=9), or CsA (n=9). Six nondiabetic placebo-treated rats were included as controls.


RESULTS
After 19 weeks of diabetes, SRL significantly decreased fibrosis as assessed by periodic acid Schiff staining and by specific extracellular matrix proteins such as fibronectin and laminin at messenger RNA and protein level compared with the diabetic placebo group. SRL ameliorated renal inflammation, glomerular hypertrophy, and podocyte loss as indicated by morphometric and immunohistological analysis. SRL lowered expression and activity of glomerular transforming growth factor-beta1/2 and vascular endothelial growth factor, all of which are considered central cytokines in the pathogenesis of diabetic nephropathy. In contrast, calcineurin phosphatase inhibition through CsA did not ameliorate any of the features of diabetic nephropathy compared with placebo treatment but slightly aggravated glomerular fibrosis without affecting transforming growth factor-beta1/2 or vascular endothelial growth factor.


CONCLUSIONS
Compared with CsA, SRL by anti-inflammatory, antifibrotic, and podocyte-protective effects clearly seems to be the superior treatment of prevention or amelioration of diabetic nephropathy in the rat.
Wittmann
Sandra
S
Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany.
Daniel
Christoph
C
Stief
Andrea
A
Vogelbacher
Regina
R
Amann
Kerstin
K
Hugo
Christian
C
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005353:Fibronectins / Q000235:genetics; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007797:Laminin / Q000235:genetics; D008297:Male; D054989:Nephrogenic Fibrosing Dermopathy / Q000517:prevention & control; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D017931:DNA Primers; D005353:Fibronectins; D007166:Immunosuppressive Agents; D007797:Laminin; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D016572:Cyclosporine; D020123:Sirolimus