Effect of Hydrocortisone on Angiotensinogen (AGT) Mutation-Causing Autosomal Recessive Renal Tubular Dysgenesis.

Min-Hua Tseng,Steven W Shaw,Ho-Yen Chueh,Tai-Wei Wu,Jhao-Jhuang Ding,Ming-Chou Chiang,Jing-Long Huang,Wen-Lang Fan,Shih-Ming Huang,Ya-Chung Tian,Martin Konrad,Shih-Hua Lin

doi:10.3390/cells10040782

Abstract

We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this AGT mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation.

Highlights

Autosomal recessive renal tubular dysgenesis (ARRTD) featured by the absence or poor-differentiation of proximal convoluted tubules on histology, maternal oligohydramnios, pulmonary hypoplasia, profound hypotension, and anuria after birth is a rare inherited disorder caused by the inactivating mutations of genes responsible for reninangiotensin system (RAS) [1,2,3,4,5,6]
HK-2 cells were transiently transfected with the indicated amount of indicated pSG5.HA.AGT plasmid DNAs and incubated for 46 h
To further examine their relative stabilities, the HK-2 cells, a proximal tubular cell line derived from normal kidney, were transiently transfected with 0.4 μg pSG5.HA.AGT and 0.8 μg pSG5.HA.AGT and transfected cells were treated with 50 μg/mL cycloheximide (CHX), a de novo protein synthesis inhibitor, for 20, 40, 80, 180, and 360 min and analyzed in the Western blot analysis for the quantitation of these AGT proteins with ImageJ software

Summary

Introduction

Autosomal recessive renal tubular dysgenesis (ARRTD) featured by the absence or poor-differentiation of proximal convoluted tubules on histology, maternal oligohydramnios, pulmonary hypoplasia, profound hypotension, and anuria after birth is a rare inherited disorder caused by the inactivating mutations of genes responsible for reninangiotensin system (RAS) [1,2,3,4,5,6]. More than 80 different mutations in genes encoding proteins of RAS have been identified in patients with ARRTD. The compromised renal perfusion caused by the defect in RAS has been proposed to be responsible for the development of renal tubular dysgenesis, the exact pathogenesis remains to be elucidated [11,12,13]. There was no definitive treatment for patients with ARRTD.

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Conclusion