Effect of Hydrocortisone on Angiotensinogen (<i>AGT</i>) Mutation–Causing Autosomal Recessive Renal Tubular Dysgenesis
Min-Hua Tseng,
Shih-Ming Huang,
Martin Konrad,
Jing-Long Huang,
Steven W. Shaw,
Ya-Chung Tian,
Ho-Yen Chueh,
Wen-Lang Fan,
Tai-Wei Wu,
Jhao-Jhuang Ding,
Ming-Chou Chiang,
Shih-Hua Lin
Affiliations
Min-Hua Tseng
Division of Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 330, Taiwan
Shih-Ming Huang
Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan
Martin Konrad
Department of General Pediatrics, University Children’s Hospital Münster, 481 Münster, Germany
Jing-Long Huang
Division of Pediatric Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 330, Taiwan
Steven W. Shaw
Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital and Chang Gung University, Taipei 114, Taiwan
Ya-Chung Tian
Division of Nephrology, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 330, Taiwan
Ho-Yen Chueh
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 330, Taiwan
Wen-Lang Fan
Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
Tai-Wei Wu
Fetal and Neonatal Institute, Division of Neonatology Children’s Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 900, USA
Jhao-Jhuang Ding
Department of Pediatrics, Tri-Service General Hospital, Taipei 114, Taiwan
Ming-Chou Chiang
Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 330, Taiwan
Shih-Hua Lin
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei 114, Taiwan
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.
