Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

Pediatr Nephrol. 2019 Sep;34(9):1493-1500. doi: 10.1007/s00467-018-4031-2. Epub 2018 Aug 11.


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.

Keywords: ADTKD; Alport syndrome; Biomarker; ER stress; Gene mutation; Nephrotic syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biomarkers / analysis
  • DNA Mutational Analysis
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Kidney Diseases / diagnosis
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / genetics
  • Kidney Diseases / pathology
  • Mutation
  • Nephrology / methods*
  • Podocytes / drug effects
  • Podocytes / pathology
  • Precision Medicine / methods*


  • Biomarkers