Expression Profiles of ITGA8 and VANGL2 Are Altered in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Jul 27

PMID 39064873

Authors

Nikola Pavlovic

Nela Kelam

Anita Racetin

Natalija Filipovic

Zenon Pogorelic

Ivana Kuzmic Prusac

Katarina Vukojevic

Affiliations

Soon will be listed here.

Abstract

Kidney failures in infants are mostly caused by congenital anomalies of the kidney and urinary tract (CAKUT), which are among the most common congenital birth disorders worldwide when paired with cardiac abnormalities. People with CAKUT often have severe kidney failure as a result of a wide range of abnormalities that can occur alone or in conjunction with other syndromic disorders. In this study, we aimed to investigate the expression pattern of CAKUT candidate genes alpha-8 integrin (ITGA8) and Van Gogh-like 2 (VANGL2) in fetal tissues of healthy and CAKUT-affected kidneys using immunohistochemistry and immunofluorescence. We found that under CAKUT circumstances, the expressions of ITGA8 and VANGL2 are changed. Additionally, we showed that VANGL2 expression is constant during fetal aging, but ITGA8 expression varies. Moreover, compared to normal healthy kidneys (CTRL), ITGA8 is poorly expressed in duplex kidneys (DKs) and dysplastic kidneys (DYS), whereas VANGL2 is substantially expressed in dysplastic kidneys (DYS) and poorly expressed in hypoplastic kidneys (HYP). These results point to VANGL2 and ITGA8 as potential prognostic indicators for CAKUT malformations. Further research is necessary to explore the molecular mechanisms underlying this differential expression of ITGA8 and VANGL2.

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References

Little M, Brennan J, Georgas K, Davies J, Davidson D, Baldock R . A high-resolution anatomical ontology of the developing murine genitourinary tract. Gene Expr Patterns. 2007; 7(6):680-99. PMC: 2117077. DOI: 10.1016/j.modgep.2007.03.002. View

Hartner A, Dotsch J . Lessons in congenital and acquired renal disease from alpha8 integrin mutant mice. Pediatr Nephrol. 2002; 17(11):882-8. DOI: 10.1007/s00467-002-0950-y. View

Lin I, Wei A, Awamleh Z, Singh M, Ning A, Herrera A . Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation. JCI Insight. 2023; 8(10). PMC: 10322691. DOI: 10.1172/jci.insight.167744. View

Brzoska H, dEsposito A, Kolatsi-Joannou M, Patel V, Igarashi P, Lei Y . Planar cell polarity genes Celsr1 and Vangl2 are necessary for kidney growth, differentiation, and rostrocaudal patterning. Kidney Int. 2016; 90(6):1274-1284. PMC: 5126096. DOI: 10.1016/j.kint.2016.07.011. View

Puvirajesinghe T, Bertucci F, Jain A, Scerbo P, Belotti E, Audebert S . Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer. Nat Commun. 2016; 7:10318. PMC: 4729931. DOI: 10.1038/ncomms10318. View

Muller U, Bossy B, Venstrom K, Reichardt L . Integrin alpha 8 beta 1 promotes attachment, cell spreading, and neurite outgrowth on fibronectin. Mol Biol Cell. 1995; 6(4):433-48. PMC: 301202. DOI: 10.1091/mbc.6.4.433. View

Humbert C, Silbermann F, Morar B, Parisot M, Zarhrate M, Masson C . Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans. Am J Hum Genet. 2014; 94(2):288-94. PMC: 3928807. DOI: 10.1016/j.ajhg.2013.12.017. View

Yates L, Papakrivopoulou J, Long D, Goggolidou P, Connolly J, Woolf A . The planar cell polarity gene Vangl2 is required for mammalian kidney-branching morphogenesis and glomerular maturation. Hum Mol Genet. 2010; 19(23):4663-76. PMC: 2972698. DOI: 10.1093/hmg/ddq397. View

Nicolaou N, Renkema K, Bongers E, Giles R, Knoers N . Genetic, environmental, and epigenetic factors involved in CAKUT. Nat Rev Nephrol. 2015; 11(12):720-31. DOI: 10.1038/nrneph.2015.140. View

10.

Papakrivopoulou E, Vasilopoulou E, Lindenmeyer M, Pacheco S, Brzoska H, Price K . Vangl2, a planar cell polarity molecule, is implicated in irreversible and reversible kidney glomerular injury. J Pathol. 2018; 246(4):485-496. PMC: 6282744. DOI: 10.1002/path.5158. View

11.

Hu Z, Xie Y, Lu J, Yang J, Zhang J, Jiang H . VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation. Sci Adv. 2023; 9(25):eadg2339. PMC: 10289648. DOI: 10.1126/sciadv.adg2339. View

12.

Chan K, Li X . Current Epigenetic Insights in Kidney Development. Genes (Basel). 2021; 12(8). PMC: 8391601. DOI: 10.3390/genes12081281. View

13.

Gomez-Conde S, Dunand O, Hummel A, Moriniere V, Gauthier M, Mesnard L . Bi-allelic pathogenic variants in ITGA8 cause slowly progressive renal disease of unknown etiology. Clin Genet. 2022; 103(1):114-118. DOI: 10.1111/cge.14229. View

14.

Lei Y, Zhang T, Li H, Wu B, Jin L, Wang H . VANGL2 mutations in human cranial neural-tube defects. N Engl J Med. 2010; 362(23):2232-5. DOI: 10.1056/NEJMc0910820. View

15.

Lozic M, Minarik L, Racetin A, Filipovic N, Saraga Babic M, Vukojevic K . , , , , and during Human Kidney Development. Int J Mol Sci. 2021; 22(17). PMC: 8431184. DOI: 10.3390/ijms22179183. View

16.

Gao B, Song H, Bishop K, Elliot G, Garrett L, English M . Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. Dev Cell. 2011; 20(2):163-76. PMC: 3062198. DOI: 10.1016/j.devcel.2011.01.001. View

17.

Rosin M, Kelam N, Juric I, Racetin A, Ogorevc M, Corre B . Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis. Int J Mol Sci. 2024; 25(8). PMC: 11049902. DOI: 10.3390/ijms25084557. View

18.

Sanna-Cherchi S, Westland R, Ghiggeri G, Gharavi A . Genetic basis of human congenital anomalies of the kidney and urinary tract. J Clin Invest. 2018; 128(1):4-15. PMC: 5749511. DOI: 10.1172/JCI95300. View

19.

Virth J, Mack H, Colville D, Crockett E, Savige J . Ocular manifestations of congenital anomalies of the kidney and urinary tract (CAKUT). Pediatr Nephrol. 2023; 39(2):357-369. PMC: 10728251. DOI: 10.1007/s00467-023-06068-9. View

20.

Schedl A . Renal abnormalities and their developmental origin. Nat Rev Genet. 2007; 8(10):791-802. DOI: 10.1038/nrg2205. View