Senescent cell accumulation and fibrosis play a fundamental role in kidney ageing. Our aim was to determine whether the angiotensin IV/insulin-regulated aminopeptidase (IRAP) axis of the renin-angiotensin system contributes to renal function decline, fibrosis and senescent cell accumulation in aged mice. We studied the role of IRAP in kidney aging using IRAP knockout mice, as well as in wildtype mice treated with an IRAP inhibitor. Complementary proximal tubule and collecting duct cell models were used to determine the mechanisms by which IRAP inhibition exerts protective effects. Glomerular filtration rate declined by 25% in wild-type mice between 3-23 months of age, concomitant with marked increases in albumin excretion, glomerulosclerosis, tubulointerstitial fibrosis and accumulation of senescent cells in the proximal tubules of the kidney. IRAP knockout mice were protected against age-related decline in glomerular filtration rate, renal fibrosis and senescence burden compared to age-matched wildtype mice. IRAP inhibition for 4 weeks (HFI-419, 500 ng/kg/min) in 28-month-old wild-type mice similarly prevented age-related decline in glomerular filtration rate and attenuated expression of cellular senescence markers. Using an in vitro model of cultured proximal tubule cells, IRAP inhibition mitigated the pro-senescent effects of oxidative stress. This was associated with shifts in the metabolic phenotype of proximal tubular cells, indicating senoprotective effects of IRAP inhibition may be mediated in part via mitochondrial function. These studies provide evidence that IRAP deficiency is protective against chronic renal cellular senescence, fibrosis and functional decline. Therefore, IRAP inhibition has therapeutic potential to attenuate pathological cardiorenal ageing through senoprotective mechanisms.
