Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline.

Autor:	Wopperer FJ; Department of Nephrology and Hypertension (F.J.W., K.X.K., K.S., M.S., R. Schmieder, K.F.H., M.S.W.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Olinger E; Center for Human Genetics, Cliniques universitaires Saint-Luc, Brussels, Belgium (E.O.).; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom (E.O., J.A.S.)., Wiesener A; Institute of Human Genetics (A.W., A.R., F.P.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Broeker KAE; Institute of Physiology (K.A.E.B.), University of Regensburg, Germany., Knaup KX; Department of Nephrology and Hypertension (F.J.W., K.X.K., K.S., M.S., R. Schmieder, K.F.H., M.S.W.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Schaefer JT; Department of Pediatrics and Adolescent Medicine (J.T.S., M.G.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Galiano M; Department of Pediatrics and Adolescent Medicine (J.T.S., M.G.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Schneider K; Department of Nephrology and Hypertension (F.J.W., K.X.K., K.S., M.S., R. Schmieder, K.F.H., M.S.W.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Schiffer M; Department of Nephrology and Hypertension (F.J.W., K.X.K., K.S., M.S., R. Schmieder, K.F.H., M.S.W.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Büttner-Herold M; Department of Nephropathology, Institute of Pathology (M.B.-H.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Reis A; Institute of Human Genetics (A.W., A.R., F.P.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Schmieder R; Department of Nephrology and Hypertension (F.J.W., K.X.K., K.S., M.S., R. Schmieder, K.F.H., M.S.W.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Pasutto F; Institute of Human Genetics (A.W., A.R., F.P.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Hilgers KF; Department of Nephrology and Hypertension (F.J.W., K.X.K., K.S., M.S., R. Schmieder, K.F.H., M.S.W.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany., Poglitsch M; Attoquant Diagnostics, Vienna, Austria (M.P.)., Ziegler C; Department of Biophysics (C.Z.), University of Regensburg, Germany., Shoemaker R; Department of Pediatrics, University of Kentucky, Lexington (R. Shoemaker)., Sayer JA; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom (E.O., J.A.S.)., Wiesener MS; Department of Nephrology and Hypertension (F.J.W., K.X.K., K.S., M.S., R. Schmieder, K.F.H., M.S.W.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
Jazyk:	angličtina
Zdroj:	Hypertension (Dallas, Tex. : 1979) [Hypertension] 2024 Sep; Vol. 81 (9), pp. 1857-1868. Date of Electronic Publication: 2024 Jul 15.
DOI:	10.1161/HYPERTENSIONAHA.124.22806
Abstrakt:	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). Competing Interests: None.
Databáze:	MEDLINE
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