Abstract
Aging kidneys are characterized by an increased vulnerability to glomerulosclerosis and a measurable decline in renal function. Evidence suggests that renal and systemic klotho and sirtuin 1 (SIRT1) deficiencies worsen kidney damage induced by exogenous stresses. The aim of this study was to explore whether resveratrol would attenuate concanavalin A (Con A)-induced renal oxidative stress and advanced glomerulosclerosis in aged mice. Aged male C57BL/6 mice were treated orally with resveratrol (30 mg/kg) seven times (12 h intervals) prior to the administration of a single tail-vein injection of Con A (20 mg/kg). The plasma and urinary levels of kidney damage markers were evaluated. The kidney histopathology, renal parameters, and oxidative stress levels were measured. Furthermore, klotho was downregulated in mouse kidney mesangial cells that were pretreated with 25 µM resveratrol followed by 20 µg/mL Con A. The urinary albumin/creatinine ratio, blood urea nitrogen, kidney mesangial matrix expansion, tubulointerstitial fibrosis, and renal levels of α-smooth muscle actin, transforming growth factor beta, fibronectin, procollagen III propeptide, and collagen type I significantly increased in Con A-treated aged mice. Aged mice kidneys also showed markedly increased levels of 8-hydroxydeoxyguanosine (8-OH-dG) and reactive oxygen species (ROS), with reduced superoxide dismutase activity and levels of glutathione, klotho, and SIRT1 after Con A challenge. Furthermore, in kidney mesangial cells, klotho silencing abolished the effects of resveratrol on the Con A-mediated elevation of the indices of oxidative stress and the expression of glomerulosclerosis-related factors. These findings suggest that resveratrol protects against Con A-induced advanced glomerulosclerosis in aged mice, ameliorating renal oxidative stress via the SIRT1-mediated klotho expression.
Highlights
Aging is a natural progressive event affecting the growth and development of living organisms
Aged kidneys are characterized by glomerulosclerosis, interstitial fibrosis, tubular atrophy, and loss of kidney function, leading to an age-related increase in the incidence of chronic kidney disease (CKD) [24]
The present study verified that resveratrol administration attenuated concanavalin A (Con A)-exacerbated albuminuria, oxidative stress, and glomerulosclerosis (Masson’s trichrome stain and increased levels in α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β, fibronectin, procollagen-III, and collagen I) in the kidney tissues of aged mice, possibly by preventing reductions in klotho and sirtuin 1 (SIRT1) levels
Summary
Aging is a natural progressive event affecting the growth and development of living organisms. Changes caused by aging represent major risk factors in the development of various diseases of the liver, heart, blood vessels, and kidney [1]. The aged kidney has an increased vulnerability to stress and a decreased ability to recover from acute kidney injury (AKI), further contributing to chronic kidney disease (CKD) [2]. Age-related renal changes include increases in mesangial matrix expansion, glomerular membrane thickening, loss of capillary loops, glomerulosclerosis, interstitial fibrosis, and tubular atrophy [3,4,5]. Aged kidneys show increased levels of oxidative stress, including 8-hydroxydeoxyguanosine (8-OH-dG) and lipid peroxidative damage-associated thiobarbituric acid-reactive substances [7,8]
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