Ginsenoside Rg1 ameliorates glomerular fibrosis during kidney aging by inhibiting NOX4 and NLRP3 inflammasome activation in SAMP8 mice
Introduction
Due to advances in modern medicine, life expectancy is increasing, which leads to an obvious increase in the population of older people. Aging can lead to significant alterations in structure and function in many organs; among them, the kidney is particularly susceptible to aging [1]. Many abnormalities of renal structure and function have been reported to be accompanied by aging, including increase of the mesangial matrix, thickening of the basement membrane, glomerular fibrosis and tubulointerstitial fibrosis [2]. Aberrant fibrogenesis impairs the homeostasis of architecture and function in the kidneys and may contribute to many end-stage renal diseases [3], which eventually results in renal failure and is harmful to health. Accordingly, it is highly important to study kidney aging and related mechanisms for the prevention of aging-related glomerular fibrosis.
The pathogenesis of aging is complicated. Overproduction of reactive oxygen species (ROS)-related oxidative stress is a main characteristic of aging. Numerous studies have shown that oxidative stress is closely associated with many age-related diseases, such as cancer [4], [5], respiratory diseases [6], skeletal muscle abnormalities [7] and chronic kidney disease [8], [9], [10]. Oxidative stress occurs when the oxidant/antioxidant balance is disrupted and excessive ROS synthesis occurs, leading to an oxidative status [11], which usually induces harmful effects, such as oxidative modification of proteins and nucleic acids and lipid peroxidation in cells [12]. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), which consists of a membrane subunit (NOX1, 2, 3, 4, or 5) and catalytic subunits of p22phox, p47phox, p67phox [13], is one of the main sources of ROS generation in many organs [14]. Studies have found that NOX4 localizes in glomerular mesangial cells, renal tubules, renal fibroblasts and podocytes and is closely involved in renal oxidative stress in kidney diseases, such as diabetic nephropathy and renal carcinoma [10], [15]. Based on the above data, we speculated that NOX4-derived ROS oxidative stress may play important roles in the development of glomerular fibrosis during kidney aging.
Inflammation is another major cause for cell aging and contributes to human diseases. Inflammation plays important roles in both mortality and morbidity in aging individuals, and almost all aging-related diseases share an inflammatory pathogenesis [16], which may also play an important role in aging-related renal damage. Inflammasomes, which have a central role in the inflammatory response, can usually be activated by diverse irritants and initiate inflammatory responses via activation of caspase-1, eventually resulting in the generation of pro-inflammatory factors [17]. Inflammasome complexes are composed of a cytosolic pattern-recognition receptor of caspase-1 and an adapter protein of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which enables interactions between the components. As the cytosolic receptors, proteins of the NOD-like (nucleotide-binding oligomerization domain) receptor (NLR) family are the major sensor proteins to form inflammasomes [18]. The NLRP3 inflammasome, due to its crucial roles in sterile and infection-triggered inflammation [18], [19], has been reported to play important roles in the evolution of renal fibrosis and contributes to the pathogenesis of acute kidney injury, chronic kidney disease and diabetic kidney disease [20], [21]. It has been reported that excessive ROS is a key signaling molecule in the progression of inflammatory disorders and plays an important role during the process of aging [22], leading to chronic inflammation [23]. In the present study, we hypothesized that NOX4 and NLRP3 inflammasome activation may induce glomerular fibrosis in the kidney with aging.
At present, there are few medicines and methods that are effective in delaying kidney aging. Ginseng has been used for more than 2000 years and is believed to be a panacea to promote longevity. There are many active components in ginseng, and numerous studies have reported that ginseng does have many beneficial effects [24], [25]. Ginsenoside Rg1 (Rg1) is the major active extract in ginseng, with anti-aging, rejuvenating, immune-potentiating and antioxidant activities [25], [26]. Currently, many studies have reported the protective effects of Rg1; for example, Rg1 can obviously suppress renal interstitial fibrosis in unilateral ureteral obstruction (UUO) rats [27] and can improve inflammation and cardiac oxidative stress in streptozotocin-induced diabetic rats [28]. However, few studies have demonstrated the protective effects of Rg1 on aging-related glomerular fibrosis by inhibiting NOX4 and NLRP3 inflammasome activation during kidney aging. In the current study, we hypothesized that Rg1 ameliorates renal fibrosis by inhibiting the activation of NOX4 and NLRP3 inflammasomes in SAMP8 mice. Additionally, because tempol can promote the metabolism of many ROS, it is often used as an ROS scavenger. Apocynin can attenuate the activity of NADPH oxidase by interfering with the intracellular translocation of p47phox and p67phox and is often used as an NOX inhibitor [29]. In this study, we observed the effects of tempol, apocynin and Rg1 on aging-related glomerular fibrosis in old SAMP8 mice and detected the activation of NOX4 and NLRP3 inflammasomes in the renal cortex during aging.
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Animals and treatment
Six-month-old male senescence-accelerated resistant mouse 1 (SAMR1) mice and male senescence-accelerated mouse prone 8 strain (SAMP8) mice (30–40 g) were provided by the Department of Laboratory Animal Science, Peking University Health Science Center. Animals were housed in an environment free from specific pathogens under the condition of 22 ± 2℃ and a 12:12 h light/dark cycle with ample food and water. The animals were divided randomly into six groups (n = 9): (1) SAMR1 control group; (2)
Effect of Rg1 treatment on renal function parameters in serum from SAMP8 mice
To investigate the protective effect of Rg1 on aging-related renal damage, biochemical parameters, including BUN and Scr, were observed in this study. After 9 weeks of drug treatment, the serum BUN and Scr levels in the SAMP8 model group were significantly higher than those in the SAMR1 control group (P < 0.01; Fig. 1A & B). Treatment with Rg1 (5, 10 mg/kg), tempol and apocynin resulted in remarkable reductions in these indexes compared with the SAMP8 group, especially in the Rg1
Discussion
Aging is the most important risk factor in many common human diseases. It has been reported that approximately half of human deaths are ascribed to chronic aging-related diseases, such as heart disease, Alzheimer’s disease (AD), cancer and chronic kidney disease (CKD) [34]. CKD has become an increasing problem across the world because it can lead to end-stage renal disease (ESRD) due to renal fibrosis, which is the principal pathological process that underlies CKD progression and ultimately
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This study was supported by the National Natural Science Foundation of China (81970630, 81671384). We would like to thank Zhirui Fang in the Department of Pharmacology and Bao Li and Dake Huang in the Synthetic Laboratory of Basic Medicine College for their technical assistance.
References (55)
- et al.
Anatomic and physiologic changes of the aging kidney
Clin. Geriatr. Med.
(2013) - et al.
Oxidative stress response and Nrf2 signaling in aging
Free Radical Biol. Med.
(2015) - et al.
NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation
Lab. Invest
(2018) - et al.
The NLRP3 inflammasome renders cell death pro-inflammatory
J. Mol. Biol.
(2018) - et al.
Bergenin impedes the generation of extracellular matrix in glomerular mesangial cells and ameliorates diabetic nephropathy in mice by inhibiting oxidative stress via the mTOR/beta-TrcP/Nrf2 pathway
Free Radical Biol. Med.
(2019) - et al.
Combined NADPH and the NOX inhibitor apocynin provides greater anti-inflammatory and neuroprotective effects in a mouse model of stroke
Free Radical Biol. Med.
(2017) - et al.
Ginsenoside Rg1, a major active component isolated from Panax notoginseng, restrains tubular epithelial to myofibroblast transition in vitro
J. Ethnopharmacol.
(2009) - et al.
Thiazolidinediones: a novel class of drugs for the prevention of diabetic nephropathy?
Kidney Int.
(2007) - et al.
TEMPOL increases NAD(+) and improves redox imbalance in obese mice
Redox Biol.
(2016) - et al.
A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1(-/)(-) mice is correlated to increased cellular senescence
Redox Biol.
(2017)
Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products
Free Radical Biol. Med.
Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases
Kidney Int.
Ginsenoside-Rg1 protects podocytes from complement mediated injury
J. Ethnopharmacol.
Ginsenoside Rg1 suppresses early stage of adipocyte development via activation of C/EBP homologous protein-10 in 3T3-L1 and attenuates fat accumulation in high fat diet-induced obese zebrafish
J. Ginseng Res.
ASC in renal collecting duct epithelial cells contributes to inflammation and injury after unilateral ureteral obstruction
Am. J. Pathol.
The aging kidney and the nephrotoxic effects of mercury, Journal of toxicology and environmental health
Part B, Crit. Rev.
MKL1 mediates TGF-beta-induced CTGF transcription to promote renal fibrosis
J. Cell. Physiol.
Mitochondrial dysfunction and oxidative stress in aging and cancer
Oncotarget
Modulation of oxidative stress as an anticancer strategy
Nat. Rev. Drug Discovery
The contribution of oxidative stress and inflamm-aging in human and equine asthma
Int. J. Mol. Sci.
Skeletal muscle aging: influence of oxidative stress and physical exercise
Oncotarget
Relationship between xanthine oxidoreductase redox and oxidative stress among chronic kidney disease patients
Oxid. Med. Cell. Longevity
Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease
Oxid. Med. Cell. Longevity
A causal link between oxidative stress and inflammation in cardiovascular and renal complications of diabetes
Clin. Sci.
Molecular mechanisms of ROS production and oxidative stress in diabetes
Biochem. J.
Localizing NADPH oxidase-derived ROS
Sci. STKE: Signal Transduction Knowl. Environ.
Ginsenoside Rg1 protects against H2O2-induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons in vitro
Int. J. Mol. Med.
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These authors contributed equally.