Enhancement of angiotensin II type 1 receptor-associated protein suppresses kidney inflammation in a mouse model of aristolochic acid nephropathy.

Chronic kidney disease generally progresses to irreversible fibrosis through chronic inflammation and age-related changes. We had previously reported that genetic knockdown of angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) exacerbates aging-associated kidney tubulointerstitial fibrosis in mice. However, whether enhanced ATRAP expression can suppress renal fibrosis and senescence in vivo remains unknown. Recently, we proposed that aristolochic acid nephropathy (AAN) could be used for modeling kidney aging with fibrosis. The present study aimed to investigate the functional role of ATRAP in aging-associated kidney fibrosis and inflammation using ATRAP transgenic (Tg19) mice subjected to AAN. AA administration caused histological renal fibrosis and enhanced ATRAP expression had no apparent effect on AA-induced renal fibrosis. However, enhanced ATRAP expression significantly suppressed AA-induced macrophage infiltration concomitant with reductions in inflammation-related, macrophage-related and senescence-related gene expression in the kidneys. Furthermore, the renal expression of anti-aging gene (Klotho, Sirtuin1) was significantly reduced in control mice in response to AA administration, whereas AA-mediated downregulation of Sirtuin1 expression was tendentially less prominent in Tg19 mice. Collectively, the enhancement of ATRAP expression failed to ameliorate renal fibrosis but partially attenuated renal inflammation and cellular senescence in AAN. Thus, ATRAP is a potential therapeutic target against renal inflammation and senescence.