AT₂R deficiency in mice accelerates podocyte dysfunction in diabetic progeny in a sex-dependent manner

The angiotensin II receptor type 2 (AT₂R) may be a potential therapeutic target for the treatment of hypertension and chronic kidney disease (CKD). The expression and function of AT₂R in the vasculature and kidney appear sexually dimorphic. We hypothesised that Agtr2 knockout dams (AT₂RKO) with gestational diabetes would program their offspring for subsequent hypertension and CKD in a sex-dependent manner.

Age- and sex-matched offspring of non-diabetic and diabetic dams of wild-type (WT) and AT₂RKO mice were followed from 4 to 20 weeks of age and were monitored for development of hypertension and nephropathy; a mouse podocyte cell line (mPOD) was also studied.

Body weight was progressively lower in female compared with male offspring throughout the lifespan. Female but not male offspring from diabetic AT₂RKO dams developed insulin resistance. Compared with the offspring of non-diabetic dams, the progeny of diabetic dams had developed more hypertension and nephropathy (apparent glomerulosclerosis with podocyte loss) at 20 weeks of age; this programming was more pronounced in the offspring of AT₂RKO diabetic dams, particularly female AT₂RKO progeny. Female AT₂RKO offspring had lower basal ACE2 glomerular expression, resulting in podocyte loss. The aberrant ACE2/ACE ratio was far more diminished in glomeruli of female progeny of diabetic AT₂RKO dams than in male progeny. Knock-down of Agtr2 in mPODs confirmed the in vivo data.

AT₂R deficiency accelerated kidney programming in female progeny of diabetic dams, possibly due to loss of protective effects of ACE2 expression in the kidney.