Wopperer, Florian J. and Olinger, Eric and Wiesener, Antje and Broeker, Katharina A. E. and Knaup, Karl X. and Schaefer, Jan T. and Galiano, Matthias and Schneider, Karen and Schiffer, Mario and Buettner-Herold, Maike and Reis, Andre and Schmieder, Roland and Pasutto, Francesca and Hilgers, Karl F. and Poglitsch, Marko and Ziegler, Christine and Shoemaker, Robin and Sayer, John A. and Wiesener, Michael S. (2024) Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline. HYPERTENSION, 81 (9). pp. 1857-1868. ISSN 0194-911X, 1524-4563
Full text not available from this repository. (Request a copy)Abstract
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).
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RENAL TUBULAR DYSGENESIS; ALDOSTERONE SYSTEM; RENIN; MUTATIONS; GENES; angiotensinogen; exome; mass spectrometry; mutation; renin-angiotensin system |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Prof. Dr. Christine Ziegler Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Armin Kurtz |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Jan 2026 07:27 |
| Last Modified: | 27 Jan 2026 07:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/64778 |
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