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Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

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Abstract

The advent of next-generation sequencing (NGS) in recent years has led to a rapid discovery of novel or rare genetic variants in human kidney cell genes, which is transforming the risk assessment, diagnosis, and treatment of kidney disease. Mutations may lead to protein misfolding, disruption of protein trafficking, and endoplasmic reticulum (ER) retention. An imbalance between the load of misfolded proteins and the folding capacity of the ER causes ER stress and unfolded protein response. Mutations in nephrin (NPHS1), podocin (NPHS2), laminin β2 (LAMB2), and α-actinin-4 (ACTN4) have been shown to induce ER stress in HEK293 cells and podocytes in hereditary nephrotic syndromes; various founder mutations in collagen IV α chains (COL4A) have been demonstrated to activate podocyte ER stress in collagen IV nephropathies; and mutations in uromodulin (UMOD) have been reported to trigger tubular ER stress in autosomal dominant tubulointerstitial kidney disease. Meanwhile, ER resident protein SEC63 may modify disease severity in autosomal dominant polycystic kidney disease. These findings underscore the importance of ER stress in the pathogenesis of monogenic kidney disease. Recently, we have identified mesencephalic astrocyte-derived neurotrophic factor (MANF) and cysteine-rich with EGF-like domains 2 (CRELD2) as urinary ER stress biomarkers in ER stress-mediated kidney diseases.

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Funding

Y.M.C. is supported by NIH grants R01 DK105056, R03DK106451, and K08DK089015, Halpin Foundation-American Society of Nephrology Research Grant, Faculty Scholar Award (MD-FR-2013-336) from the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital, Clinical Scientist Development Award (2015100) from the Doris Duke Charitable Foundation, Career Development Award from the Nephrotic Syndrome Study Network (NEPTUNE), Early Career Development Award from the Central Society for Clinical and Translational Research (CSCTR), and Renal Translational Innovation Grant from Washington University Division of Nephrology. Y.M.C. is a member of Washington University Diabetes Research Center (supported by NIH P30 DK020579), Washington University Musculoskeletal Research Center (supported by NIH P30AR057235), and Washington University Institute of Clinical and Translational Sciences (UL1 TR000448).

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Correspondence to Ying Maggie Chen.

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A patent application entitled “Mesencephalic astrocyte-derived neurotrophic factor (MANF) as a urine biomarker for endoplasmic reticulum (ER) stress-related kidney disease, methods and uses therefore” has been filed by Y.M. Chen and Washington University Office of Technology Management (serial no. 14730465, filed on June 4, 2015). Another patent application entitled “Methods of detecting biomarkers of endoplasmic reticulum (ER) stress-associated kidney diseases” has been filed by Y.M. Chen and Y. Kim and Washington University Office of Technology Management (serial no. 15664476, filed on July 31, 2017).

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Park, SJ., Kim, Y. & Chen, Y.M. Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology. Pediatr Nephrol 34, 1493–1500 (2019). https://doi.org/10.1007/s00467-018-4031-2

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