Upregulation of C/EBP Homologous Protein induced by ER Stress Mediates Epithelial to Myofibroblast Transformation in ADTKD-UMOD

Wang, Dan; Qiu, Yagui; Fan, Jinjin; Liu, Yuanying; Chen, Wenfang; Li, Zhijian; Chen, Wei; Wang, Xin

doi:10.7150/ijms.65036

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Int J Med Sci 2022; 19(2):364-376. doi:10.7150/ijms.65036 This issue Cite

Research Paper

Upregulation of C/EBP Homologous Protein induced by ER Stress Mediates Epithelial to Myofibroblast Transformation in ADTKD-UMOD

Dan Wang^1,2*, Yagui Qiu^1,2*, Jinjin Fan^1,2, Yuanying Liu^1,2, Wenfang Chen³, Zhijian Li^1,2, Wei Chen^1,2✉, Xin Wang^1,2✉

1. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, China.
2. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, China.
3. Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, China.
*These authors have contributed equally to this work and share first authorship.

Citation:

Wang D, Qiu Y, Fan J, Liu Y, Chen W, Li Z, Chen W, Wang X. Upregulation of C/EBP Homologous Protein induced by ER Stress Mediates Epithelial to Myofibroblast Transformation in ADTKD-UMOD. Int J Med Sci 2022; 19(2):364-376. doi:10.7150/ijms.65036. https://www.medsci.org/v19p0364.htm

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Abstract

Autosomal dominant tubulointerstitial kidney disease due to UMOD mutations (ADTKD-UMOD) results in chronic interstitial nephritis, which gradually develops into end-stage renal disease. It is believed that the accumulation of mutant uromodulin causes the endoplasmic reticulum (ER) stress, then leads to the kidney damage. But the underlying mechanism remains unclear. To find the ADTKD-UMOD patients, UMOD gene screening was performed in 26 patients with unexplained chronic interstitial nephritis, during the past 10 years in our department, and among them three ADTKD-UMOD cases were discovered. Routine pathological staining and electron microscopy sections were reviewed again to confirm their kidney lesions. Immunostaining of UMOD and ER stress marker GRP78, as well as CHOP have all been done. The strong colocalization of UMOD with GRP78 and CHOP in ADTKD-UMOD patients but not in other chronic interstitial nephritis patients had been found. Moreover in vitro experiments, ER stress induced by tunicamycin (TM) not only significantly increased the expression of GRP78 and CHOP, but also caused the epithelial to myofibroblast transformation (EMT) of renal tubular epithelial cells, evidenced by decreased expression of E-cadherin and increased expression of vimentin, and extracellular matrix (ECM) deposition, evidenced by increased expression of fibronectin (FN). CHOP knockdown could restore the upregulation of vimentin and FN induced by TM. Thus, specific activation of CHOP in renal tubular epithelial cells induced by UMOD protein might be the key reason of renal interstitial fibrosis in ADTKD-UMOD patients.

Keywords: CHOP, ER stress, EMT, ADTKD-UMOD, Renal fibrosis

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APA

Wang, D., Qiu, Y., Fan, J., Liu, Y., Chen, W., Li, Z., Chen, W., Wang, X. (2022). Upregulation of C/EBP Homologous Protein induced by ER Stress Mediates Epithelial to Myofibroblast Transformation in ADTKD-UMOD. International Journal of Medical Sciences, 19(2), 364-376. https://doi.org/10.7150/ijms.65036.

ACS

Wang, D.; Qiu, Y.; Fan, J.; Liu, Y.; Chen, W.; Li, Z.; Chen, W.; Wang, X. Upregulation of C/EBP Homologous Protein induced by ER Stress Mediates Epithelial to Myofibroblast Transformation in ADTKD-UMOD. Int. J. Med. Sci. 2022, 19 (2), 364-376. DOI: 10.7150/ijms.65036.

NLM

CSE

Wang D, Qiu Y, Fan J, Liu Y, Chen W, Li Z, Chen W, Wang X. 2022. Upregulation of C/EBP Homologous Protein induced by ER Stress Mediates Epithelial to Myofibroblast Transformation in ADTKD-UMOD. Int J Med Sci. 19(2):364-376.

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