Abstract
The progress in the research field of diabetic kidney disease (DKD) has been disturbed by the lack of reliable animal models. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R and selectively inhibits pathological AT1R signaling. In this study, we investigated whether overactivation of the renin-angiotensin system (RAS) through a combination of ATRAP deletion with Ang II stimulation developed a progressive DKD model in C57BL/6 mice, which are resistant to the development of kidney injury. Eight-week-old male systemic ATRAP-knockout mice on the C57BL/6 strain (KO) and their littermate wild-type mice (Ctrl) were divided into five groups: 1) Ctrl, 2) Ctrl-streptozotocin (STZ), 3) KO-STZ, 4) Ctrl-STZ-Ang II, and 5) KO-STZ-Ang II. Ang II was administered for 6 weeks from 4 weeks after STZ administration. At 10 weeks after STZ administration, mice were euthanized to evaluate kidney injuries after measurements of systolic blood pressure (SBP) and urinary albumin excretion (UAE). Neither ATRAP deletion alone nor Ang II stimulation alone developed a progressive DKD model in STZ-induced diabetic C57BL/6 mice (UAE, Ctrl vs Ctrl-STZ vs KO-STZ vs Ctrl-STZ-Ang II: 10.6±2.0 vs 89.0±11.9 vs 69.1±15.0 vs 151.3±55.4 μg/day). However, a combination of ATRAP deletion with Ang II stimulation accelerated the development of DKD as manifested by overt albuminuria (UAE, KO-STZ-Ang II: 852.0±195.6 μg/day, p <0.001 vs Ctrl-STZ-Ang II), glomerular hypertrophy, podocyte loss, mesangial expansion, kidney interstitial fibrosis, and functional insufficiency, concomitant with increased angiotensinogen and AT1R expression in the kidneys. SBP levels were comparable between the Ctrl-STZ-Ang II and KO-STZ-Ang II groups (SBP, Ctrl-STZ-Ang II vs KO-STZ-Ang II: 144±4 vs 154±5 mmHg, p =0.363). In STZ-induced diabetic C57BL/6 mice, the combination of ATRAP deletion and Ang II stimulation accelerates the development of DKD by converting the C57BL/6 strain from being nephropathy-resistant to -susceptible, which may be associated with intrarenal RAS overactivation.
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