Abstract 4115634: Potential Role for Circadian Disruption in Acute Kidney Injury-driven Cardiovascular Disease

Background/Hypothesis: Circadian disruption and AKI, even if kidney function recovers, are linked to an increased risk of CVD and death. We explored the hypothesis that AKI was associated with CVD through circadian disruption. Approach: Sixteen ~25-week-old PER2::Luciferase (a real-time reporter of circadian rhythm) C57BL/6J male mice had micro-clamps applied to both renal pedicles for ~26 minutes to produce a recoverable AKI. Three animals underwent a sham procedure. Three animals had to be euthanized all others had serum creatinine (Scr) measured on day 2. Twelve weeks after surgery, all animals (n=13) were euthanized. Results: The sham group's day 2 Scr (n=3; mean 0.10 [range 0.08 - 0.15]) was unchanged from baseline (0.11 [0.07 - 0.18]). Based on the day 2 Scr, 3 mice were classified as having mild/moderate AKI (Scr increased ≤ 3-fold) (0.16 [0.08 - 0.20]) and 7 as having severe AKI (Scr increased > 3-fold) (0.98 [0.26 - 1.93]). By 12 weeks post-AKI, the Scr (0.16 [0.1 - 0.2 mg/dl]) of all animals returned to a level statistically similar to baseline. Immunohistochemistry demonstrated that 6 of 7 mice with severe AKI had atherosclerotic-like lesions in the aortic root (A), sinus, or coronaries (B): 4 mice had lesions averaging 9,754.7 µm 2 and 2 mice had coronary artery lumen narrowing averaging 56.2%. Similar lesions were found in 1 of 3 mice with mild/moderate AKI, but no lesions were found in the sham animals (C). The lesions had CD45+ cells on their surface and in the adventitia (A inset), but were devoid of CD68+ and SMC alpha-actin+ cells. In the neointima, SMC alpha-actin+ cells predominated (B inset). Mouse liver, lung, adrenal gland, renal cortex, outer and inner medulla were collected at 15:00 and analyzed for 5 days by Lumicycle. Circadian rhythms were evaluated with JTK_CYCLE. No apparent AKI-dependent differences were observed in the liver, lung, adrenal, or renal outer medulla. However, the amplitude of renal inner medulla rhythms decreased with AKI (P = 0.008), while the amplitude of renal cortex increased with AKI (P = 0.01, E&F). Conclusions: This is the first report of an AKI model resulting in atherosclerosis-like lesions in wild-type mice without the need for a high-fat diet, genetic manipulation, or further provocation. The lesions were associated with a disruption of the intrarenal circadian rhythms. We will discuss the implications of this research as well as the metabolic consequences of the circadian disruption.