Cyclosporine and rapamycin act in a synergistic and dose-dependent manner in a model of immunosuppressant-induced kidney damage
| Autor: | G.R. Bicknell, Nicholas R. Brook, J R Waller, M. L. Nicholson |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Male
Dose dependence Administration Oral Pharmacology Kidney Excretion Rats Sprague-Dawley chemistry.chemical_compound medicine Animals RNA Messenger Sirius Red Antibacterial agent Sirolimus Creatinine Transplantation business.industry Chemistry Drug Synergism Diet Sodium-Restricted Ciclosporin Rats medicine.anatomical_structure Gene Expression Regulation Toxicity Immunology Cyclosporine Surgery business Immunosuppressive Agents medicine.drug |
| Zdroj: | Transplantation proceedings. 37(2) |
| ISSN: | 0041-1345 |
| Popis: | The combination of cyclosporine (CSA) and rapamycin (RAPA) is a potent and commonly used approach to immunosuppression following solid-organ transplantation. By applying varying doses of CSA and RAPA to the rat salt-depleted model, we aimed to find a dose combination that favored antiproliferation/antifibrosis rather than toxicity. Male Sprague-Dawley rats (350 to 500 g) were salt-depleted for 7 days prior to commencing CSA and RAPA treatment. Serum creatinine and urinary protein/creatinine ratios were measured. Fibrosis was estimated with Sirius red staining of extracellular collagen. mRNA expression of TGF-β, MMP-2, MMP-9, TIMP-1, and collagen III was assessed with reverse transcriptase PCR. A rise in serum creatinine at 7 and 28 days was observed for CSA 15 mg/kg/d (P = .002) but not CSA 7.5 mg (P = .06) or RAPA 1 mg (P = .69) compared to controls. Twenty-four-hour urinary protein excretion was unchanged compared to controls for all drug doses and combinations. Of the dose combinations, CSA 7.5 mg/d + RAPA 0.5 mg/d produced the lowest serum creatinine for all time points, and inhibited profibrotic TIMP-1 (P = .017), while increasing antifibrotic MMP-2 (P = .009) mRNA expression, compared to CSA treatment alone. Expression of TGF-β and collagen III was unaltered between groups. CSA treatment produced molecular and biochemical changes indicating renal damage. Addition of RAPA can attenuate this damage, but only with a dose reduction of both agents. The most favorable results were for the dose combination CSA 7.5 mg/kg/d plus RAPA 0.5 mg/kg/d. |
| Databáze: | OpenAIRE |
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