Obesity and dyslipidemia can be associated with cellular senescence, and may impair
kidney function. However, whether senescence contributes to renal dysfunction in these
conditions remains unclear. Quercetin is an abundant dietary flavonoid that selectively
clears inhibiting PI3K/AKT and p53/p21/serpines and inducing apoptosis. We hypothesized that high-fat-diet-induced obesity
causes renal senescence, which would be mitigated by quercetin. C57BL/6J mice fed
either standard chow or high-fat diets (HFDs) were treated with quercetin (50 mg/kg)
or vehicle 5-days biweekly via oral gavage for 10 weeks. Subsequently, renal function
was studied in vivo using magnetic resonance imaging, and renal senescence and histology
were evaluated ex vivo. Mice fed with a HFD developed obesity and hypercholesterolemia,
whereas renal size remained unchanged. Murine obesity impaired renal function and
cortical oxygenation, and induced glomerulomegaly. Renal markers of senescence (eg,
expression of p16, p19, and p53) and its secretory phenotype were upregulated in the obese hypercholesterolemic compared
to lean mice in renal tubular cells, but attenuated in quercetin-treated murine kidneys,
as was renal fibrosis. Quercetin treatment also increased renal cortical oxygenation
and decreased plasma creatinine levels in obese mice, whereas body weight and cholesterol
levels were unaltered. Therefore, murine obesity and dyslipidemia induce renal tissue
senescence and impairs kidney function, which is alleviated by chronic senolytic treatment.
These findings implicate senescence in loss of kidney function in murine dyslipidemia
and obesity, and support further studies of senolytic therapy in obesity.
Abbreviations:
BF (bright field), BOLD (blood oxygen level-dependent), BP (blood pressure), FISP (Fast Imaging with Steady Precession), HFD (high-fat diet), MGE (multi-echo gradient echo), MRI (magnetic resonance imaging), MT (Masson's trichrome), PAS (Periodic acid-Schiff), PCR (polymerase chain reaction), SA-β-Gal (senescence-associated β-Galactosidase), SASP (senescence-associated secretory phenotype), SCAPs (senescent cell anti-apoptotic pathways), TUNEL (Terminal deoxynucleotidyl transferase dUTP nick-end labeling), X-Gal (5-bromo-4-chloro-3-indolyl-b-D-galactopyranoside)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Obesity and risk for chronic renal failure.J Am Soc Nephrol. 2006; 17: 1695-1702
- Fat tissue, aging, and cellular senescence.Aging cell. 2010; 9: 667-684
- A crucial role for adipose tissue p53 in the regulation of insulin resistance.Nat Med. 2009; 15: 1082-1087
- Hepatic cellular senescence pathway genes are induced through histone modifications in a diet-induced obese rat model.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G558-G564
- Cellular senescence and the senescent secretory phenotype: therapeutic opportunities.J Clin Invest. 2013; 123: 966-972
- New agents that target senescent cells: the flavone, fisetin, and the bcl-xl inhibitors, a1331852 and a1155463.Aging. 2017; 9: 955-963
- Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation.Kidney Int. 2017; 92: 114-124
- The achilles' heel of senescent cells: from transcriptome to senolytic drugs.Aging Cell. 2015; 14: 644-658
- Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.Aging cell. 2016; 15: 973-977
- Evolution of cardiac and renal impairment detected by high-field cardiovascular magnetic resonance in mice with renal artery stenosis.J Cardiovasc Magn Reson. 2013; 15: 98
- Noninvasive assessment of renal fibrosis with magnetization transfer mr imaging: validation and evaluation in murine renal artery stenosis.Radiology. 2017; 283: 77-86
- Temporal analysis of signaling pathways activated in a murine model of two-kidney, one-clip hypertension.Am J Physiol Renal Physiol. 2009; 297: F1055-F1068
- The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration.Nephrol Dial Transplant. 2012; 27: 3110-3119
- Naturally occurring p16(ink4a)-positive cells shorten healthy lifespan.Nature. 2016; 530: 184-189
- Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening.Kidney Int. 2003; 63: 2134-2143
- Circulating and renal vein levels of micrornas in patients with renal artery stenosis.Nephrol Dial Transplant. 2015; 30: 480-490
- The mitochondrial-targeted peptide, ss-31, improves glomerular architecture in mice of advanced age.Kidney Int. 2017; 91: 1126-1145
- Renal injury in the extremely obese patients with normal renal function.Kidney Int. 2008; 73: 947-955
- Beneficial effects of an alternating high- fat dietary regimen on systemic insulin resistance, hepatic and renal inflammation and renal function.PLoS One. 2012; 7: e45866
- Magnetic resonance elastography noninvasively detects in vivo renal medullary fibrosis secondary to swine renal artery stenosis.Invest Radiol. 2013; 48: 61-68
- Microalbuminuria in obese patients with or without hypertension.Int J Obes Relat Metab Disord. 1996; 20: 574-579
- Obesity correlates with glomerulomegaly but is not associated with kidney dysfunction early after donation.Transplant Direct. 2015; 1: 1-6
- Effects of insulin on rat renal microvessels: studies in the isolated perfused hydronephrotic kidney.Kidney Int. 1997; 51: 1507-1513
- Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption.J Am Soc Nephrol. 1999; 10: 2569-2576
- Glomerular hyperfiltration and the salt paradox in early [corrected] type 1 diabetes mellitus: a tubulo-centric view.J Am Soc Nephrol. 2003; 14: 530-537
- The metabolic syndrome and chronic kidney disease.Transl Res. 2017; 183: 14-25
- Lipid droplet accumulation is associated with an increase in hyperglycemia-induced renal damage: prevention by liver x receptors.Am J Pathol. 2013; 182: 727-741
- Beta cell aging markers have heterogeneous distribution and are induced by insulin resistance.Cell Metab. 2017; 25: 898-910.e5
- Relationship of p53 accumulation in peripheral tissues of high-fat diet-induced obese rats with decrease in metabolic and oncogenic signaling of insulin.Gen Comp Endocrinol. 2015; 214: 134-139
- Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy.Am J Physiol Renal Physiol. 2008; 295: F1563-F1573
- Glp-1 and ghrelin attenuate high glucose/high lipid-induced apoptosis and senescence of human microvascular endothelial cells.Cell Physiol Biochem. 2017; 44: 1842-1855
- Feedback between p21 and reactive oxygen production is necessary for cell senescence.Mol Syst Biol. 2010; 6: 347
- P38mapk is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.EMBO J. 2011; 30: 1536-1548
- Leptin changes differentiation fate and induces senescence in chondrogenic progenitor cells.Cell Death Dis. 2016; 7: e2188
- Cyclin-dependent kinase inhibitor p21(waf1): contemporary view on its role in senescence and oncogenesis.Biochemistry. 2012; 77: 575-584
- Megalin-mediated tubuloglomerular alterations in high-fat diet-induced kidney disease.J Am Soc Nephrol. 2016; 27: 1996-2008
- Cellular senescence: a translational perspective.EBioMedicine. 2017; 21: 21-28
- Cellular senescence drives age-dependent hepatic steatosis.Nat Commun. 2017; 8: 15691
- Senolytics improve physical function and increase lifespan in old age.Nat Med. 2018; 24: 1246-1256
- Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice.Nutr Res Pract. 2012; 6: 201-207
- Chronic dietary intake of quercetin alleviates hepatic fat accumulation associated with consumption of a western-style diet in c57/bl6j mice.Mol Nutr Food Res. 2011; 55: 530-540
- The clinical potential of senolytic drugs.J Am Geriatr Soc. 2017; 65: 2297-2301
- Pharmacokinetics and bioavailability of quercetin glycosides in humans.J Clin Pharmacol. 2001; 41: 492-499
- Elimination of p19(arf) -expressing cells protects against pulmonary emphysema in mice.Aging cell. 2018; 17: e12827
Article info
Publication history
Published online: July 15, 2019
Accepted:
July 11,
2019
Received in revised form:
July 5,
2019
Received:
December 20,
2018
Identification
Copyright
© 2019 Elsevier Inc. All rights reserved.
