Ochratoxin A induced differentiation nephrotoxicity in renal tubule and glomeruli via autophagy differential regulation
Graphical Abstract
Introduction
Ochratoxin A (OTA) is a mycotoxin produced by fungi strains of Aspergillus and Penicillium (van der Merwe et al., 1965). OTA contaminant widely occurs in various food commodities due to its stable physicochemical property, such as fruits, cereals, eggs, meat and wine, etc (Malir et al., 2016). Nephrotoxicity is mainly caused by OTA exposure, numerous human renal diseases are thought to relate with OTA exposure, including Balkan endemic nephropathy and chronic interstitial nephropathy (Yordanova et al., 2010, Maaroufi et al., 1995). In addition, the preliminary study reported that orally fed with 40 ppm OTA for 24 months induces renal adenomas in male mice, and OTA is classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer (IARC) in 1993 (Ochratoxin, 1993, Bendele et al., 1985). So far, there are no specific therapy methods for OTA poisoning. Renal fibrosis consisting in the replacement of normal renal interstitium with accumulated deposition of extracellular matrix (ECM), it represents a common phenomenon of kidney injury in amost all progressive forms of renal diseases (Panizo et al., 2021). With the OTA exposure, body fibroblast is transformed into myofibroblasts (characterized by production the proteins of α-SMA). The myofibroblasts exhibits a state of continuous synthesis and deposition of ECM components, the abnormal accumulation of ECM could lead to renal fibrosis and finally result in chronic kidney disease (CKD) (Humphreys, 2018). The renal tubules injury related to OTA exposure had been well documented since it is discovered in 1965. It is reported that OTA exposure induces epithelial cells injury, morphological changes and renal tubule fibrosis in numerous mammal (Li et al., 2021a, Marin et al., 2019, Ringot et al., 2006). Besides, our recent study also proveed that OTA exposure induces the fragmentation and atrophy in mice glomeruli (Le et al., 2020). It is well known that glomeruli and renal tubule play essential but different roles in body metabolism. Filtration function is dominated by glomeruli, while reabsorption function is dominated by renal tubules (Osborn et al., 2021). However, to our knowledge, the previous studies related to OTA-induced nephrotoxicity are mainly focusing on its single nephrotoxicity in renal tubule or glomeruli, the comparison toxicity between it is still unknown.
Autophagy is a eukaryotic conserved pathway that mediates the degradation of aging proteins and recycle damaged organelles to maintaining cellular homeostasis (Mizushima and Komatsu, 2011, Myerowitz et al., 2021). In the meantime, autophagy plays a crucial role in the toxicity induced by various mycotoxin exposure, including OTA. Previous study shown that OTA induces cytoprotective autophagy in PK-15 cells (Qian et al., 2018). Besides, in recently studies, it has been reported a type of select-autophagy, with a differentiation gene and protein expressive abundance in different tissues, is implicating in various diseases, including tumorigenesis, metabolic disorders as well as mycotoxin injury (Li et al., 2021b, Zaffagnini and Martens, 2016, Su et al., 2019). Up to now, the relationship between autophagy abundance expressive in glomeruli, renal tubule and OTA-induced nephrotoxicity remains veiled.
Since it is uncovered in 1965, research related to OTA-induced nephrotoxicity is mainly specific in glomeruli or renal tubule (Le et al., 2020, Pyo et al., 2020). However, its comparison nephrotoxicity is still unknown. Exploring the specific pathological process of OTA-induced nephrotoxicity may contribute to the accurate therapeutic and develop novel target drugs for mitigating OTA poisoning. In the present study, C57BL/6 mice, HK-2 cells and HGMC cells were adapted as the vehicles in vivo and in vitro to explore OTA-induced differentiation nephrotoxicity in glomeruli and renal tubule, and further investigated its potential mechanisms.
Section snippets
Reagents
OTA (purity ≥ 98 %) (32937), MTT (M2003), chloroquine (C6628), rapamycin (R0935) and rabbit anti-LC3B antibody (L7543) were purchased from Sigma-Aldrich (St. Louis, USA). Nonyl Acridine Orange (A1372) was purchased from Thermo Fisher Scientific (Waltham, MA, USA). Horseradish peroxidase (HRP)-conjugated goat anti-rabbit (7076) and rabbit anti-β-actin (4970) were purchased from Cell signaling Technology (Boston, USA). Rabbit anti-TGF-β1 (A15103) was purchased from ABclonal, (Wuhan, China).
OTA exposure damaged kidney function in mice
All mice were accommodated for a week, and with a normal appearance before the experiment. After that, mice were intraperitoneally (i.p) treated with 0, 0.5, 1 and 2 mg/kg b.w. OTA on alternate days for twenty-one days. The daily weight gain (Fig. 1A) and the average daily feed intake (Fig. 1B) were recorded. Our results showed that the body weight and feed intake were decreased in OTA treatment group when compared with control group.
After monitoring mice physiological indicators for 21 days,
Discussion
Ochratoxin A (OTA) contamination is a serious problem all over the world due to its stable chemistry and worldwide distribution, which causes huge food health risk to human and animal (Malir et al., 2016, Tao et al., 2018). OTA exposure mainly causes nephrotoxicity, and its single toxic effect specific in glomeruli or renal tubule has been well investigated since it is discovered in 1965 (Li et al., 2021a, Le et al., 2020). However, the comparison toxicity of OTA exposure in glomeruli and renal
Conclusion
In vivo, a discrepant kidney injury was induced in mice glomeruli and renal tubule with OTA exposure. In vitro, OTA-induced cytotoxicity in cells derived from renal tubule is higher than its from glomeruli, and the differentiation cytotoxicity is relate to cellular autophagy differential regulation.
Ethical Statement
Procedure involving mice is conducted according to the guideline of European Guidelines for Animal Welfare and approved by the Committee for the Care and Use of Wenzhou Institute, University of Chinese Academy of Sciences (Animal Ethics Number: SYXK (Zhe) 2021–0040).
CRediT authorship contribution statement
All the authors listed have approved the manuscript and approved the submission of the manuscript. Author contribution as follows: Guannan Le: Conceptualization, Methodology, Validation, Formal analysis, Writing – original draft, Writing – review & editing, Visualization. Heng Du: Formal analysis, Writing – original draft. Lili Hou: Conceptualization, Data curation. Ardache Sylia: Writing – original draft, Writing – review & editing. Azhar Mohammed: Writing – original draft, Writing – review &
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We are very grateful to Prof. Rongshan Li (Provincial People’s Hospital of Shanxi Medical University; Shanxi, China) for providing Human glomerular mesangial cell line.
This work was funded by the National Natural Science Foundation of China (31772811, 32072926).
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