Background: MRP2 (multiple drug resistance-associated protein 2) is a xenobiotic transport protein that includes cyclosporine A. (CyA). MRP2 is downregulated in minimal change nephrosis (MCN) and membranous nephropathy by miRNA133a binding to its 3UTR region, which is triggered by endothelin-1 (ET-1) via the ETB-receptor (MN). The status of CyA as a therapy option for focal-segmental sclerosis (FSGS) is yet uncertain. In addition, the mechanism of CyA nephrotoxicity in renal transplantation is unknown. Co-morbidities/clinical factors, the morphological extent of MR2 destruction, and the role of miRNA133a in nephrotoxicity have all remained uninvestigated. The goal of this study is to look at co-morbidities, as well as the function of ET-1 and miRNA133a in the development of CyA renal toxicity and FSGS. Methods: Co-morbidities and clinical variables were examined in 230 samples from 124 patients. Immune histology and subsequent morphometry of MRP2 expression were done in 35 CyA patients (tubular damage, arteriolar damage, no damage; plus 5 cases of so-called null biopsies as controls), and a qRT-PCR for the detection of miRNA133a was investigated in FSGS (n=8) patients. ET-1, alone or in conjunction with CyA, was tested on MRP2 and miRNA133a levels in human proximal tubular cell culture. The levels of miRNA in the ETB-receptor knock-out rat (ETBR sl/s) were also assessed. Results: CyA nephrotoxicity was not caused by any single clinical parameter. Morphometric examination demonstrated an increasing degree of damage, ranging from no CyA toxicity through arteriolar CyA toxicity to combined arteriolar and tubular toxicity, with tubular toxicity being the most severe. The effect was investigated in human proximal tubular cell culture, where the combination of ET-1 and CyA caused more tubular damage than ET-1 alone. CyA caused tubular but also arteriolar damage by upregulating miRNA133a and downregulating the mrp2 gene. Mrp2 was downregulate by qRT-PCR in FSGS, with just a modest alteration to normal conditions identified by immunological histology. Conclusion: MiRNA133a-mediated downregulation of MRP2 is a key mechanism of CyA nephrotoxicity and FSGS. If FSGS is treated with CyA, the severity of cytotoxicity may rise. The use of urinary analysis as a detection tool and the use of an ETB-receptor antagonist as a therapy option are described. The therapeutic potential of steroid resistant syndromes, such as FSGS in African children, is discussed.
Author (S) Details
Dr med. Sandra Stefanikova
Department of Carciac Surgery, Insespital, Bern, Switzerland.
Dr med. Joe Schankin
Department of Pathology, University Hospital of Cologne, Cologne, Germany.
PD Dr. rer medic. Melanie von Brandenstein
Department of Urology, University Hospital of Cologne, Cologne, Germany.
Reinhard Büttner
Department of Pathology, University Hospital of Cologne, Cologne, Germany.
Dr. med Heike Goebel
Department of Pathology, University Hospital of Cologne, Cologne, Germany.
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