Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology
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.
KeywordsER stress Nephrotic syndrome Alport syndrome ADTKD Gene mutation Biomarker
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).
Compliance with ethical standards
Conflict of interest
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).
- 5.Burman A, Tanjore H, Blackwell TS (2018) Endoplasmic reticulum stress in pulmonary fibrosis. Matrix Biol. https://doi.org/10.1016/j.matbio.2018.03.015
- 9.Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J, Hasselbacher K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F (2007) Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 119:e907–e919CrossRefPubMedGoogle Scholar
- 18.Matejas V, Hinkes B, Alkandari F, Al-Gazali L, Annexstad E, Aytac MB, Barrow M, Blahova K, Bockenhauer D, Cheong HI, Maruniak-Chudek I, Cochat P, Dotsch J, Gajjar P, Hennekam RC, Janssen F, Kagan M, Kariminejad A, Kemper MJ, Koenig J, Kogan J, Kroes HY, Kuwertz-Broking E, Lewanda AF, Medeira A, Muscheites J, Niaudet P, Pierson M, Saggar A, Seaver L, Suri M, Tsygin A, Wuhl E, Zurowska A, Uebe S, Hildebrandt F, Antignac C, Zenker M (2010) Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum. Hum Mutat 31:992–1002CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, Engel J, Engvall E, Hohenester E, Jones JCR, Kleinman HK, Marinkovich MP, Martin GR, Mayer U, Meneguzzi G, Miner JH, Miyazaki K, Patarroyo M, Paulsson M, Quaranta V, Sanes JR, Sasaki T, Sekiguchi K, Sorokin LM, Talts JF, Tryggvason K, Uitto J, Virtanen I, von der Mark K, Wewer UM, Yamada Y, Yurchenco PD (2005) A simplified laminin nomenclature. Matrix Biol 24:326–332CrossRefPubMedGoogle Scholar
- 31.Pieri M, Stefanou C, Zaravinos A, Erguler K, Stylianou K, Lapathitis G, Karaiskos C, Savva I, Paraskeva R, Dweep H, Sticht C, Anastasiadou N, Zouvani I, Goumenos D, Felekkis K, Saleem M, Voskarides K, Gretz N, Deltas C (2014) Evidence for activation of the unfolded protein response in collagen IV nephropathies. J Am Soc Nephrol 25:260–275CrossRefPubMedGoogle Scholar
- 33.Papazachariou L, Demosthenous P, Pieri M, Papagregoriou G, Savva I, Stavrou C, Zavros M, Athanasiou Y, Ioannou K, Patsias C, Panagides A, Potamitis C, Demetriou K, Prikis M, Hadjigavriel M, Kkolou M, Loukaidou P, Pastelli A, Michael A, Lazarou A, Arsali M, Damianou L, Goutziamani I, Soloukides A, Yioukas L, Elia A, Zouvani I, Polycarpou P, Pierides A, Voskarides K, Deltas C (2014) Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing. PLoS One 9:e115015CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Eckardt KU, Alper SL, Antignac C, Bleyer AJ, Chauveau D, Dahan K, Deltas C, Hosking A, Kmoch S, Rampoldi L, Wiesener M, Wolf MT, Devuyst O (2015) Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—a KDIGO consensus report. Kidney Int 88:676–683CrossRefPubMedGoogle Scholar
- 38.Brunati M, Perucca S, Han L, Cattaneo A, Consolato F, Andolfo A, Schaeffer C, Olinger E, Peng JH, Santambrogio S, Perrier R, Li S, Bokhove M, Bachi A, Hummler E, Devuyst O, Wu QY, Jovine L, Rampoldi L (2015) The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin. Elife. https://doi.org/10.7554/eLife.08887
- 39.Bernascone I, Janas S, Ikehata M, Trudu M, Corbelli A, Schaeffer C, Rastaldi MP, Devuyst O, Rampoldi L (2010) A transgenic mouse model for uromodulin-associated kidney diseases shows specific tubulo-interstitial damage, urinary concentrating defect and renal failure. Hum Mol Genet 19:2998–3010CrossRefPubMedGoogle Scholar
- 41.Kemter E, Prueckl P, Sklenak S, Rathkolb B, Habermann FA, Hans W, Gailus-Durner V, Fuchs H, de Angelis MH, Wolf E, Aigner B, Wanke R (2013) Type of uromodulin mutation and allelic status influence onset and severity of uromodulin-associated kidney disease in mice. Hum Mol Genet 22:4148–4163CrossRefPubMedGoogle Scholar
- 43.Vylet'al P, Kublova M, Kalbacova M, Hodanova K, Baresova V, Stiburkova B, Sikora J, Hulkova H, Zivny J, Majewski J, Simmonds A, Fryns JP, Venkat-Raman G, Elleder M, Kmoch S (2006) Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int 70:1155–1169CrossRefPubMedGoogle Scholar
- 48.Kim Y, Park SJ, Manson SR, Molina CA, Kidd K, Thiessen-Philbrook H, Perry RJ, Liapis H, Kmoch S, Parikh CR, Bleyer AJ, Chen YM (2017) Elevated urinary CRELD2 is associated with endoplasmic reticulum stress-mediated kidney disease. JCI Insight. https://doi.org/10.1172/jci.insight.92896
- 51.Tadimalla A, Belmont PJ, Thuerauf DJ, Glassy MS, Martindale JJ, Gude N, Sussman MA, Glembotski CC (2008) Mesencephalic astrocyte-derived neurotrophic factor is an ischemia-inducible secreted endoplasmic reticulum stress response protein in the heart. Circ Res 103:1249–1258CrossRefPubMedPubMedCentralGoogle Scholar