From autosomal recessive renal tubular dysgenesis to the renin-angiotensin system

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Marie Claire Gubler , Olivier Gribouval, Corinne Antignac, Annie Michaud and Pierre Corvol

INSERM U 1163, Institute Imagine, Hospital Necker Enfants Malades, France
CIRB, College de France, France

: J Nephrol Ren Dis

Abstract

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Renal tubular dysgenesis (RTD) is a severe disorder of renal development characterized by early onset foetal anuria leading to persistent oligohydramnios with the resulting sequence of malformations including lung hypoplasia. The usual issue is foetal or post-natal death due to hypotension, anuria and respiratory distress. Absence of differentiated proximal tubules is the hallmark of the disease. Familial cases, with an autosomal recessive inheritance, are frequent. Histological analysis of renal tissues directed us toward the renin-angiotensin system (RAS). Accordingly, genetic investigation confirmed that hereditary RDT was linked to mutations in the AGT, REN, ACE and AGTR1 genes. The absence of functional RAS leads to foetal and neonatal hypotension, renal hypoperfusion, and the development of anuria and tubular dysgenesis. Interestingly, DTR is also observed in foetuses exposed to RAS blockers, and in various pathological conditions leading to chronic renal hypoperfusion such as severe cardiopathies, hepatic failure or in the donor foetus in the twin-to-twin transfusion syndrome. By expressing the mutations in cellular models, progresses in the knowledge of the structure-function relationship of the proteins have been obtained notably by showing that the defective misfolded proteins undergo either intracellular accumulation and retention or rapid degradation. These studies also confirmed that ACE has to be anchored in the plasma membrane to be active. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis. II. Image: Renin expression in a patient with ACE homozygous mutation

Biography

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Marie Claire Gubler Gribouval performed the genetic analysis of the RAS genes in the Laboratory of Hereditary Kidney Diseases (INSERM U 1163) headed by C Antignac. A Michaud performed the in vitro expression of the mutations in the laboratory headed by P Corvol. MC Gubler is the pathologist at the origin of the work.