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

Abstract

Aims/hypothesis The angiotensin II receptor type 2 (AT 2 R) may be a potential therapeutic target for the treatment of hypertension and chronic kidney disease (CKD). The expression and function of AT 2 R in the vasculature and kidney appear sexually dimorphic. We hypothesised that Agtr2 knockout dams (AT 2 RKO) with gestational diabetes would program their offspring for subsequent hypertension and CKD in a sex-dependent manner. Methods Age-and sex-matched offspring of non-diabetic and diabetic dams of wild-type (WT) and AT 2 RKO 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. Results Body weight was progressively lower in female compared with male offspring throughout the lifespan. Female but not male offspring from diabetic AT 2 RKO 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 AT 2 RKO diabetic dams, particularly female AT 2 RKO progeny. Female AT 2 RKO 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 AT 2 RKO dams than in male progeny. Knock-down of Agtr2 in mPODs confirmed the in vivo data. Conclusions/interpretation AT 2 R deficiency accelerated kidney programming in female progeny of diabetic dams, possibly due to loss of protective effects of ACE2 expression in the kidney.

Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia

“…When children aged 5–18 years were affected, urinary calcium and magnesium excretion was lower in O-T1DM ( 79 ). In animal models, widespread interstitial fibrosis ( 80 ) and severe glomerulosclerosis ( 71 , 81 ) with functional glomeruli loss ( 82 , 83 ) were present at different periods in maternal diabetic offspring, leading to a decreased creatinine clearance ( 87 ), an increased glomerular filtration rate ( 88 ), and microalbuminuria ( 80 ). Urinary calcium and magnesium output was less ( 84 , 85 ), similar to the excretion of basal sodium and urine volume ( 86 ).…”

“…Urinary calcium and magnesium output was less ( 84 , 85 ), similar to the excretion of basal sodium and urine volume ( 86 ). Apart from this fact, activation of the intrarenal renin–angiotensin system (RAS), together with intrarenal dopamine receptor phosphorylation ( 86 ) and increased transforming growth factor-β1 ( Tgf β 1 ) ( 80 ), was evident in the cortex of hypertensive offspring of diabetic mothers ( 80 , 82 , 88 , 89 ).…”