TY - JOUR
T1 - Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline
AU - Wopperer, Florian J.
AU - Olinger, Eric
AU - Wiesener, Antje
AU - Broeker, Katharina A.E.
AU - Knaup, Karl X.
AU - Schaefer, Jan T.
AU - Galiano, Matthias
AU - Schneider, Karen
AU - Schiffer, Mario
AU - Büttner-Herold, Maike
AU - Reis, André
AU - Schmieder, Roland
AU - Pasutto, Francesca
AU - Hilgers, Karl F.
AU - Poglitsch, Marko
AU - Ziegler, Christine
AU - Shoemaker, Robin
AU - Sayer, John A.
AU - Wiesener, Michael S.
N1 - Publisher Copyright:
© 2024 American Heart Association, Inc.
PY - 2024/9/1
Y1 - 2024/9/1
N2 - BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). 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 RAS was assessed by comprehensive biochemical analysis in blood. Renin 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 renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. 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 RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin 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).
AB - BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). 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 RAS was assessed by comprehensive biochemical analysis in blood. Renin 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 renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. 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 RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin 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).
KW - angiotensinogen
KW - exome
KW - mass spectrometry
KW - mutation
KW - renin-angiotensin system
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U2 - 10.1161/HYPERTENSIONAHA.124.22806
DO - 10.1161/HYPERTENSIONAHA.124.22806
M3 - Article
C2 - 39005223
AN - SCOPUS:85199103976
SN - 0194-911X
VL - 81
SP - 1857
EP - 1868
JO - Hypertension
JF - Hypertension
IS - 9
ER -