Metabolic syndrome-induced tubulointerstitial injury: Role of oxidative stress and preventive effects of acetaminophen

Abstract

The prevalence of metabolic syndrome persistently increases and affects over 30% of U.S. adults. To study how metabolic syndrome may induce tubulointerstitial injury and whether acetaminophen has renal-protective properties, 4-week-old obese Zucker rats were randomly assigned into three groups, control (OC), vehicle dimethyl sulfoxide (OV), and acetaminophen treatment (30 mg/kg/day for 26 weeks), and lean Zucker rats served as healthy controls. Significant tubulointerstitial injuries were observed in both OC and OV animals, evidenced by increased tubular cell death, tubular atrophy/dilation, inflammatory cell infiltration, and fibrosis. These tubulointerstitial alterations were significantly reduced by treatment with a chronic but low dose of acetaminophen, which acted to diminish NADPH oxidase isoforms Nox2 and Nox4 and decrease tubulointerstitial oxidative stress (reduced tissue superoxide and macromolecular oxidation). Decreased oxidative stress by acetaminophen was paralleled by the reduction of tubular proapoptotic signaling (diminished Bax/Bcl-2 ratio and caspase 3 activation) and the alleviation of tubular epithelial-to-mesenchymal transition (decreased transforming growth factor β, connective tissue growth factor, α-smooth muscle actin, and laminin). These data suggest that increased oxidative stress plays a critical role in mediating metabolic syndrome-induced tubulointerstitial injury and provide the first evidence suggesting that acetaminophen may be of therapeutic benefit for the prevention of tubulointerstitial injury.

Acetaminophen Attenuates Obesity-Related Renal Injury Through ER-Mediated Stress Mechanisms

“…5B). Similar results of altered TUNEL-positive cells were found in the tubulointerstitium of obese rats as reported previously [13]. …”

“…After a week for environmental acclimation, the obese Zucker rats were randomly assigned into one of three groups (n = 6 each): obese control (OC), obese vehicle (OV, 0.073 mL DMSO/kg/d), or obese treated with acetaminophen (OT). Acetaminophen (30mg/kg/d) was dissolved in DMSO and then provided to animals via drinking water for 26 weeks as described previously [13]. Age-matched lean Zucker rats were used as controls (LC, n = 6).…”

“…Apoptosis was assessed using a transferase-mediated dUTP nick-end labeling (TUNEL) kit (Roche Applied Science, Indianapolis, IN) as described previously [13,14]. Images were captured using an Olympus BX51 fluorescence microscope (Olympus America, Melville, NY) at 400 × magnification.…”

“…Total protein extracts were prepared and immunoblotting was performed as previously described [13,17,18]. Primary antibodies included anti-GRP78 (#ab21685), anti-CHOP (#sc-575), anti-phospho-eIF2α (#3597S; Cell Signaling Technology (CST), Danvers, MA), anti-eIF2α (#9722; CST), anti-ATF4 (#ab1371; Abcam), anti-caspase 12 (#ab62484; Abcam), anti-c-Jun N-terminal kinase (JNK, #9252; CST), anti-phospho-JNK (#9251S; CST), and anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH, #2118; CST).…”

Acetaminophen attenuates glomerulosclerosis in obese Zucker rats via reactive oxygen species/p38MAPK signaling pathways

“…Acetaminophen (N-acetyl-p-aminophenol; APAP) is a widely used analgesic and antipyretic drug that exhibits antioxidant activity [9][10][11][12][13][14][15][16][17]. Whether acetaminophen is effective in the prevention of metabolic syndrome-associated glomerulosclerosis has, to our knowledge, not been examined.…”