Introduction: This study assessed dexamethasone as rescue therapy for fatal autosomal recessive renal tubular dysgenesis (ARRTD) due to AGT mutation, with conditional knockout mice enabling targeted investigation of AGT's role and precise evaluation of treatment.Methods: A novel homozygous AGTE3-4del/E3-4del conditional knock-in mouse model, bearing a 2870 bp deletion encompassing exons 3 and 4 of AGT, was used to evaluate the in vivo therapeutic impact of prenatal dexamethasone administration.Results: AGTE3-4del/E3-4del mice exhibited classic features of ARRTD, including hypotension, elevated serum creatinine and urea, and high postnatal mortality, reduced body weight, electrolyte disturbances, and impaired urine concentration.Histological analysis revealed defective proximal tubular development and pronounced renal dysgenesis.Molecular studies demonstrated almost absent hepatic AGT mRNA and protein expression, accompanied by decreased circulating AGT and angiotensin II levels, and a significant increase in renin concentrations.Prenatal dexamethasone treatment enhanced hepatic AGT production, reduced renin, and partially restored proximal tubule maturation of AGTE3-4del/E3-4delmice, demonstrating beneficial effects on both renal development and molecular abnormalities in this fatal genetic model.Conclusion: AGT is very crucial in maintaining renin-angiotensin system homeostasis and supporting normal kidney development.Antenatal dexamethasone administration can partially ameliorate renal and molecular abnormalities caused by AGT mutation-induced ARRTD.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
Saito et al. (Wed,) studied this question.