Prenatal dexamethasone partially rescues renal tubular dysgenesis in a germline Agt -deletion mouse model

Hypothesis/Introduction Given higher neonatal mortality associated with autosomal recessive renal tubular dysgenesis (ARRTD), this study investigated the role of AGT mutations and evaluated the therapeutic efficacy of prenatal dexamethasone. Materials and Methods A germline Agt exon 3–4 deletion mouse model bearing a 2791-bp deletion encompassing exons 3 and 4 was generated. Eleven mice (3 wild-type, 4 heterozygous, 4 homozygous) underwent phenotyping at 24 weeks. Pregnant heterozygous dams received subcutaneous dexamethasone (1 mg/kg/day) or vehicle, and offspring were analysed at postnatal day 1 by quantitative RT-PCR, immunoblotting, ELISA and Lotus Tetragonolobus Lectin (LTL) immunofluorescence. Groups were compared by Student's two-tailed t test. Results Agt ΔE3–4/ΔE3–4 mice exhibited hypotension, elevated serum creatinine and urea, high postnatal mortality and impaired urine concentration. Histology revealed defective proximal tubular development. Hepatic Agt mRNA was near-undetectable and hepatic AGT protein markedly reduced, accompanied by decreased circulating AGT and angiotensin II and increased renin. Prenatal dexamethasone enhanced hepatic AGT production, reduced renin, and partially restored proximal tubule maturation. Conclusions This study shows AGT is crucial for maintaining renin-angiotensin system homeostasis and supporting normal kidney development, and provides in vivo evidence that prenatal dexamethasone can partially reverse the fatal renal and molecular defects caused by AGT mutation-induced ARRTD.