Abstract
Cyclosporine A (CsA) extracted from the products of fungal fermentation is used to develop a chronic nephropathy model. However, it has numerous side effects. Ochratoxin A (OTA) is a mycotoxin that induces renal injury. We developed a chronic nephropathy model to lessen the side effects of CsA by administration of nontoxic dosage of OTA, and investigated the underlying mechanism. C57BL/10 wild-type mice, toll-like receptor 4 (TLR4)−/− mice, and HK-2 cells were used in this study. The nontoxic dosage (0.25 mg/kg, qod) of OTA could significantly decrease the dosage of CsA from 30 to 20 mg/kg per day, and combination of them induced chronic nephropathy model and alleviated the side effects of onefold CsA in vivo, including cardiotoxicity, hepatotoxicity, and immunosuppression. The nontoxic concentration (0.5 μg/ml) of OTA could significantly decrease the concentration of CsA from 10 to 6 μg/ml that induced cytotoxicity, oxidative stress, and nephrotoxicity in vitro. Nontoxic concentration of OTA and low dosage of CsA activated TLR4 and autophagy. These toxic effects induced by OTA and CsA could be reversed by knockdown of TLR4 and autophagy inhibitor 3-methyladenine in vitro. Furthermore, the renal injury and autophagy induced by OTA and CsA could be attenuated in TLR4−/− mice. It suggested that a chronic nephropathy model had been successfully developed by administration of nontoxic concentration of OTA and low dosage of CsA via TLR4-mediated autophagy. The side effects of current model were significantly lesser than those of the previous model induced by onefold CsA. It provided a new tool for exploring the pathogenesis and treatment of chronic kidney disease.
Highlights
Introduction CyclosporineA (CsA) extracted from the products of fungal fermentation is commonly used in organ transplant patients, since the early 1980’s
Following treatment for 28 d, kidney index was apparently decreased and kidney injury was increased in the group of 0.5 mg/kg per day ochratoxin A (OTA) as compared with the control group, and the group of 0.25 mg/kg per day OTA had no significant change (Supplementary Fig. 1)
Hematoxylin and eosin (H&E) staining in groups E and F showed that partial renal tubular structural changes and a small number of inflammatory cells in the tubule interstitium as compared to control group (Fig. 1b)
Summary
A (CsA) extracted from the products of fungal fermentation is commonly used in organ transplant patients, since the early 1980’s It mainly acts on the antirejection response of transplantation[1]. Hou et al Cell Death and Disease (2020)11:153 cardiotoxicity, neurotoxicity, and hypertension[8,9,10] Based on these studies, we speculated whether the adverse effects of CsA on other tissues and organs could be mitigated by reducing the amount of CsA. Ochratoxin is a mycotoxin that acquires worldwide attention after aflatoxin It is an important kind of mycotoxins and produced by both Aspergillus and Penicillium[11,12]. Among this group, ochratoxin A (OTA) is a nephrotoxic member, which is main causative agent of human Balkan endemic nephropathy[13]. We hypothesized that nontoxic dose of OTA could probably decrease the dose of CsA to induce chronic nephropathy model as well
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