Increased Severity of AKI in Obese Mice

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Background: Obesity is a lipotoxic state of abnormal and excessive fat accumulation. Although obesity is a well-known risk factor for chronic kidney disease, its role in acute kidney injury (AKI) is not well understood. We conducted this study to investigate the impact of obesity from a high fat diet (HFD) on AKI using the folic acid nephropathy (FAN) model. Methods: Male mice aged 6-8-week-old received either HFD or control diet (CD) for 6 weeks. AKI was induced using FAN, in which intraperitoneal folic acid is given at 240 ug/g. Control mice were administered vehicle. Kidneys and bloods were collected 48 hours post FAN. Results: HFD mice demonstrated more severe AKI compared to CD mice post FAN as evidenced by worse serum urea (HFD 48.9±4.9 mmol/L vs CD 32.3±19.8 mmol/L, P=0.035) (Fig 1A), worse creatinine (HFD 0.09±0.08 mmol/L vs CD 0.03±0.014 mmol/L, P=0.022), increased NGAL expression by Western blot (HFD 10.8±4.8-fold vs CD 2.1±1.3-fold) (Fig 1B) and RT-PCR (HFD 303.2±117.5-fold vs CD 184±77.6-fold, P=0.004). RT-PCR found that HFD increased the expression of inflammatory markers after FAN with increased IL-6 (HFD 214.6± 23.3-fold vs CD 108±87.8-fold, P = 0.014) and increased MCP-1 (HFD 32.3± 15.9-fold vs CD 12.8±8.5-fold, P<0.001). HFD mice showed worse histological injury score after FAN (HFD 3.43±0.6 vs CD 2.27±0.9, P<0.001). Notably, HFD increased tubular vacuolation in both FAN (HFD 3.5±0.6 vs CD 2.34±0.6, P<0.001) and vehicle treated (HFD 3.25±0.8 vs CD 1.93±0.4, P< 0.001) consistent with lipid accumulation in tubular epithelial cells (TEC). Conclusion: Our data indicate that obese mice accumulate lipid in tubular epithelal cells and develop more severe AKI and inflammation following FAN. Strategies to reduce obesity may improve outcomes in AKI. Funding: Government Support – Non-U.S.Figure 1.

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