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Lookup NU author(s): Florian Wopperer, Dr Eric Olinger, Professor John SayerORCiD
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© 2024 American Heart Association, Inc. BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the REN (renin)angiotensin system. Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The REN-angiotensin system was assessed by comprehensive biochemical analysis in blood. REN expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma REN concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of REN. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the renin-angiotensin system in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of REN in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).
Author(s): Wopperer FJ, Olinger E, Wiesener A, Broeker KAE, Knaup KX, Schaefer JT, Galiano M, Schneider K, Schiffer M, Buttner-Herold M, Reis A, Schmieder R, Pasutto F, Hilgers KF, Poglitsch M, Ziegler C, Shoemaker R, Sayer JA, Wiesener MS
Publication type: Article
Publication status: Published
Journal: Hypertension
Year: 2024
Volume: 81
Issue: 9
Pages: 1857 - 1868
Online publication date: 15/07/2024
Acceptance date: 25/06/2024
ISSN (print): 0194-911X
ISSN (electronic): 1524-4563
Publisher: Lippincott Williams and Wilkins
URL: https://doi.org/10.1161/HYPERTENSIONAHA.124.22806
DOI: 10.1161/HYPERTENSIONAHA.124.22806
PubMed id: 39005223
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