Prebiotic prevents impaired kidney and renal Oat3 functions in obese rats

in Journal of Endocrinology
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Obesity is health issue worldwide, which can lead to kidney dysfunction. Prebiotics are non-digestible foods that have beneficial effects on health. This study aimed to investigate the effects of xylooligosaccharide (XOS) on renal function, renal organic anion transporter 3 (Oat3) and the mechanisms involved. High-fat diet was provided for 12 weeks in male Wistar rats. After that, the rats were divided into normal diet (ND); normal diet treated with XOS (NDX); high-fat diet (HF) and high-fat diet treated with XOS (HFX). XOS was given daily at a dose of 1000 mg for 12 weeks. At week 24, HF rats showed a significant increase in obesity and insulin resistance associated with podocyte injury, increased microalbuminuria, decreased creatinine clearance and impaired Oat3 function. These alterations were improved by XOS supplementation. Renal MDA level and the expression of AT1R, NOX4, p67phox, 4-HNE, phosphorylated PKCα and ERK1/2 were significantly decreased after XOS treatment. In addition, Nrf2-Keap1 pathway, SOD2 and GCLC expression as well as renal apoptosis were also significantly reduced by XOS. These data suggest that XOS could indirectly restore renal function and Oat3 function via the reduction of oxidative stress and apoptosis through the modulating of AT1R-PKCα-NOXs activation in obese insulin-resistant rats. These attenuations were instigated by the improvement of obesity, hyperlipidemia and insulin resistance.

 

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    Effect of XOS on insulin resistance. Plasma glucose levels at the time intervals after glucose ingestion (A). Total area under the curve of OGTT (B). Data are mean ± s.e.m. (n = 5/group). Multiple comparison was performed by one-way ANOVA followed by Fisher’s least significant difference test. *P < 0.05 compared with the control group. P < 0.05 compared with control treated with XOS. P < 0.05 compared with the high-fat diet group. HF, high-fat diet; HFX, XOS-treated HF diet groups; ND, control; NDX, control treated with XOS.

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    Effect of XOS on renal Oat3 function and expression. [3H]ES uptake into renal cortical tissues was calculated and expressed as a percentage of the control (A). Immunoblot of Oat3 protein expression in whole cell lysate (B) and membrane fraction (C) of renal cortical tissues normalized to β-actin. Na+-K+ ATPase expression was shown to represent the membrane fraction of kidney tissue. Values are shown as mean ± s.e.m. (n = 5–6/group and four renal slices per animal were used). One-way ANOVA followed by Fisher’s least significant difference test was used for multiple comparison. *P < 0.05 compared with the control group. P < 0.05 compared with control treated with XOS. P < 0.05 compared with the high-fat diet group. HF, high-fat diet; HFX, XOS-treated HF diet groups; ND, control; NDX, control treated with XOS.

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    The effect of XOS treatment on renal morphology and podocyte injury. Hematoxylin and eosin stain (scale bar = 200 μm) of the kidney tissues (A). The kidney injury score (B). The expression of podocin (C) and nephrin (D) normalized to β-actin. Na+-K+ ATPase expression was shown to represent the membrane fraction of kidney tissue. The kidney injury score was graded from the enlargement of Bowman’s capsule (E), glomerular atrophy (black arrow), increased interstitial space (asterisks) and the sloughing of cells into tubular lumen (head arrow). Data are mean ± s.e.m. (n = 5/group). Multiple comparison of the score is calculated by One-way ANOVA followed by Fisher’s least significant difference test. *P < 0.05 compared with the control group. P < 0.05 compared with control treated with XOS. P < 0.05 compared with the high-fat diet group. HF, high-fat diet; HFX, XOS-treated HF diet groups; ND, control; NDX, control treated with XOS. A full color version of this figure is available at https://doi.org/10.1530/JOE-17-0471.

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    Effect of XOS on renal ROS production. End products of renal lipid peroxidation were shown as renal cortical malondialdehyde (MDA) (A) and 4-HNE expression normalized to GAPDH (B). Values are shown as mean ± s.e.m. (n = 5–6/group). One-way ANOVA followed by Fisher’s least significant difference test was used for multiple comparison. *P < 0.05 compared with the control group. P < 0.05 compared with control treated with XOS. P < 0.05 compared with the high-fat diet group. HF, high-fat diet; HFX, XOS-treated HF diet groups; ND, control; NDX, control treated with XOS.

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    Effect of XOS on proteins involved in renal oxidative stress. Immunoblot of AT1R (A), PKCα (B), phosphorylated PKCα (C), NOX4 (D) and p67phox (E) protein expression in renal cortical tissues normalized to β-actin or GAPDH. Values are shown as mean ± s.e.m. (n = 5–6/group). One-way ANOVA followed by Fisher’s least significant difference test was used for multiple comparison. *P < 0.05 compared with the control group. P < 0.05 compared with control treated with XOS. P < 0.05 compared with the high-fat diet group. HF, high-fat diet; HFX, XOS-treated HF diet groups; ND, control; NDX, control treated with XOS.

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    Effect of XOS on protein expression of the renal oxidative stress defense mechanism. Immunoblot of whole cell Nrf2 (A), Nuclear Nrf2 (B), Keap1 (C), Erk1/2 (D), SOD2 (E) and GCLC (F) protein expression in renal cortical tissues normalized to β-actin. Values are shown as mean ± s.e.m. (n = 5–6/group). One-way ANOVA followed by Fisher’s least significant difference test was used for multiple comparison. *P < 0.05 compared with the control group. P < 0.05 compared with control treated with XOS. P < 0.05 compared with the high-fat diet group. HF, high-fat diet; HFX, XOS-treated HF diet groups; ND, control; NDX, control treated with XOS.

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    Effect of XOS on renal apoptosis. TUNEL staining of kidney tissue (scale bar = 100 μm) and quantitative result of the number of TUNEL positive cells (n = 5/group and five fields per animal were used) (A). Expression of proapoptotic protein Bax (B), anti-apoptotic protein Bcl-2 (C) normalized to β-actin and Bax/Bcl-2 expression ratio (D). Values are shown as mean + s.e.m. (n = 5–6/group). One-way ANOVA followed by Fisher’s least significant difference test was used for multiple comparison. *P < 0.05 compared with the control group. P < 0.05 compared with control treated with XOS. P < 0.05 compared with the high-fat diet group. HF, high-fat diet; HFX, XOS-treated HF diet groups; ND, control; NDX, control treated with XOS. A full color version of this figure is available at https://doi.org/10.1530/JOE-17-0471.

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    A proposed signaling model of obesity-induced renal injury and dysfunction and the effect of XOS treatment. Obesity activates renal RAS activation which then stimulates NOXs activity via phosphorylated PKCα. NOXs stimulate ROS production, resulting in increased renal oxidative stress and antioxidant enzyme expression mediated by ERK1/2 pathway. Renal apoptosis is also increased by oxidative stress. Phosphorylated PKCα can also induce internalization of Oat3 transporters in the proximal tubules leading to Oat3 dysfunction. XOS treatment for 12 weeks can reduce obesity and insulin resistance that contribute to an attenuation of these impaired signaling pathways and improvement of renal function. A full color version of this figure is available at https://doi.org/10.1530/JOE-17-0471.

References

BaxmannACAhmedMSMarquesNCMenonVBPereiraABKirsztajnGMHeilbergIP 2008 Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C. Clinical Journal of the American Society of Nephrology 3 348354. (https://doi.org/10.2215/CJN.02870707)

BedardKKrauseKH 2007 The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiological Reviews 87 245313. (https://doi.org/10.1152/physrev.00044.2005)

BushKTWuWLunCNigamSK 2017 The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut-liver-kidney axis. Journal of Biological Chemistry 292 1578915803. (https://doi.org/10.1074/jbc.M117.796516)

ChabrashviliTTojoAOnozatoMLKitiyakaraCQuinnMTFujitaTWelchWJWilcoxCS 2002 Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. Hypertension 39 269274. (https://doi.org/10.1161/hy0202.103264)

ChristensenEGLichtTRLeserTDBahlMI 2014 Dietary xylo-oligosaccharide stimulates intestinal bifidobacteria and lactobacilli but has limited effect on intestinal integrity in rats. BMC Research Notes 7 660. (https://doi.org/10.1186/1756-0500-7-660)

ClunyNLEllerLKKeenanCMReimerRASharkeyKA 2015 Interactive effects of oligofructose and obesity predisposition on gut hormones and microbiota in diet-induced obese rats. Obesity 23 769778. (https://doi.org/10.1002/oby.21017)

CulletonBFLarsonMGEvansJCWilsonPWBarrettBJParfreyPSLevyD 1999 Prevalence and correlates of elevated serum creatinine levels: the Framingham Heart Study. Archives of Internal Medicine 159 17851790. (https://doi.org/10.1001/archinte.159.15.1785)

DuanPLiSYouG 2010 Angiotensin II inhibits activity of human organic anion transporter 3 through activation of protein kinase Calpha: accelerating endocytosis of the transporter. European Journal of Pharmacology 627 4955. (https://doi.org/10.1016/j.ejphar.2009.10.048)

FazeliGStopperHSchinzelRNiCWJoHSchuppN 2012 Angiotensin II induces DNA damage via AT1 receptor and NADPH oxidase isoform Nox4. Mutagenesis 27 673681. (https://doi.org/10.1093/mutage/ges033)

Fernandez-SanchezAMadrigal-SantillanEBautistaMEsquivel-SotoJMorales-GonzalezAEsquivel-ChirinoCDurante-MontielISanchez-RiveraGValadez-VegaCMorales-GonzalezJA 2011 Inflammation, oxidative stress, and obesity. International Journal of Molecular Sciences 12 31173132. (https://doi.org/10.3390/ijms12053117)

FurukawaSFujitaTShimabukuroMIwakiMYamadaYNakajimaYNakayamaOMakishimaMMatsudaMShimomuraI 2004 Increased oxidative stress in obesity and its impact on metabolic syndrome. Journal of Clinical Investigation 114 17521761. (https://doi.org/10.1172/JCI21625)

GarridoAMGriendlingKK 2009 NADPH oxidases and angiotensin II receptor signaling. Molecular and Cellular Endocrinology 302 148158. (https://doi.org/10.1016/j.mce.2008.11.003)

GeisztMKoppJBVarnaiPLetoTL 2000 Identification of renox, an NAD(P)H oxidase in kidney. PNAS 97 80108014. (https://doi.org/10.1073/pnas.130135897)

GibsonGRProbertHMLooJVRastallRARoberfroidMB 2004 Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutrition Research Reviews 17 259275. (https://doi.org/10.1079/NRR200479)

GobinathDMadhuANPrashantGSrinivasanKPrapullaSG 2010 Beneficial effect of xylo-oligosaccharides and fructo-oligosaccharides in streptozotocin-induced diabetic rats. British Journal of Nutrition 104 4047. (https://doi.org/10.1017/S0007114510000243)

GriendlingKKMinieriCAOllerenshawJDAlexanderRW 1994 Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circulation Research 74 11411148. (https://doi.org/10.1161/01.RES.74.6.1141)

HamiltonMKRonveauxCCRustBMNewmanJWHawleyMBarileDMillsDARaybouldHE 2017 Prebiotic milk oligosaccharides prevent development of obese phenotype, impairment of gut permeability, and microbial dysbiosis in high fat-fed mice. American Journal of Physiology: Gastrointestinal and Liver Physiology 312 G474G487. (https://doi.org/10.1152/ajpgi.00427.2016)

HenegarJRBiglerSAHenegarLKTyagiSCHallJE 2001 Functional and structural changes in the kidney in the early stages of obesity. Journal of the American Society of Nephrology 12 12111217.

HongHZengJSKreulenDLKaufmanDIChenAF 2006 Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke. American Journal of Physiology: Heart and Circulatory Physiology 291 H2210H2215. (https://doi.org/10.1152/ajpheart.01270.2005)

HuJTiwariSRiaziSHuXWangXEcelbargerCM 2009 Regulation of angiotensin II type I receptor (AT1R) protein levels in the obese Zucker rat kidney and urine. Clinical and Experimental Hypertension 31 4963. (https://doi.org/10.1080/10641960802409788)

JaikumkaoKPongchaidechaAChattipakornNChatsudthipongVPromsanSArjinajarnPLungkaphinA 2016 Atorvastatin improves renal organic anion transporter 3 and renal function in gentamicin-induced nephrotoxicity in rats. Experimental Physiology 101 743753. (https://doi.org/10.1113/EP085571)

JainIKumarVSatyanarayanaT 2015 Xylooligosaccharides: an economical prebiotic from agroresidues and their health benefits. Indian Journal of Experimental Biology 53 131142.

JolesJAKunterUJanssenUKrizWRabelinkTJKoomansHAFloegeJ 2000 Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats. Journal of the American Society of Nephrology 11 669683.

KimYMKimSJTatsunamiRYamamuraHFukaiTUshio-FukaiM 2017 ROS-induced ROS release orchestrated by Nox4, Nox2 and mitochondria in VEGF signaling and angiogenesis. American Journal of Physiology: Cell Physiology 312 C749C764. (https://doi.org/10.1152/ajpcell.00346.2016)

KoppleJDFerozeU 2011 The effect of obesity on chronic kidney disease. Journal of Renal Nutrition 21 6671. (https://doi.org/10.1053/j.jrn.2010.10.009)

LeyREBackhedFTurnbaughPLozuponeCAKnightRDGordonJI 2005 Obesity alters gut microbial ecology. PNAS 102 1107011075. (https://doi.org/10.1073/pnas.0504978102)

LiZSummanenPHKomoriyaTFinegoldSM 2015 In vitro study of the prebiotic xylooligosaccharide (XOS) on the growth of Bifidobacterium spp and Lactobacillus spp. International Journal of Food Sciences and Nutrition 66 919922. (https://doi.org/10.3109/09637486.2015.1064869)

LiuHCJamshidiNChenYEralySAChoSYBhatnagarVWuWBushKTAbagyanRPalssonBO 2016 An organic anion transporter 1 (OAT1)-centered metabolic network. Journal of Biological Chemistry 291 1947419486. (https://doi.org/10.1074/jbc.M116.745216)

Lopez-GiacomanSMaderoM 2015 Biomarkers in chronic kidney disease, from kidney function to kidney damage. World Journal of Nephrology 4 5773. (https://doi.org/10.5527/wjn.v4.i1.57)

LungkaphinAArjinajarnPPongchaidechaASrimaroengCChatsudthipongLChatsudthipongV 2014 Impaired insulin signaling affects renal organic anion transporter 3 (Oat3) function in streptozotocin-induced diabetic rats. PLoS ONE 9 e96236. (https://doi.org/10.1371/journal.pone.0096236)

LuoHWangXChenCWangJZouXLiCXuZYangXShiWZengC 2015 Oxidative stress causes imbalance of renal renin angiotensin system (RAS) components and hypertension in obese Zucker rats. Journal of the American Heart Association 4 e001559. (https://doi.org/10.1161/JAHA.114.001559)

MotohashiHSakuraiYSaitoHMasudaSUrakamiYGotoMFukatsuAOgawaOInuiK 2002 Gene expression levels and immunolocalization of organic ion transporters in the human kidney. Journal of the American Society of Nephrology 13 866874.

NgHYYisireyiliMSaitoSLeeCTAdelibiekeYNishijimaFNiwaT 2014 Indoxyl sulfate downregulates expression of Mas receptor via OAT3/AhR/Stat3 pathway in proximal tubular cells. PLoS ONE 9 e91517. (https://doi.org/10.1371/journal.pone.0091517)

NigamSK 2015 What do drug transporters really do? Nature Reviews Drug Discovery 14 2944. (https://doi.org/10.1038/nrd4461)

NigamSKBushKTMartovetskyGAhnSYLiuHCRichardEBhatnagarVWuW 2015 The organic anion transporter (OAT) family: a systems biology perspective. Physiological Reviews 95 83123. (https://doi.org/10.1152/physrev.00025.2013)

PapadimitriouAPeixotoEBSilvaKCLopes de FariaJMLopes de FariaJB 2014 Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGFbeta-1 signaling. Journal of Nutritional Biochemistry 25 773784. (https://doi.org/10.1016/j.jnutbio.2014.03.010)

ParnellJAReimerRA 2009 Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. American Journal of Clinical Nutrition 89 17511759. (https://doi.org/10.3945/ajcn.2009.27465)

PereiraMAKartashovAIEbbelingCBVan HornLSlatteryMLJacobsDRJrLudwigDS 2005 Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet 365 3642. (https://doi.org/10.1016/S0140-6736(04)17663-0)

PhatchawanAChutimaSVaranujCAnusornL 2014 Decreased renal organic anion transporter 3 expression in type 1 diabetic rats. American Journal of the Medical Sciences 347 221227. (https://doi.org/10.1097/MAJ.0b013e3182831740)

Pourghassem GargariBDehghanPAliasgharzadehAAsghari Jafar-AbadiM 2013 Effects of high performance inulin supplementation on glycemic control and antioxidant status in women with type 2 diabetes. Journal of Diabetes and Metabolism 37 140148. (https://doi.org/10.4093/dmj.2013.37.2.140)

PrenticeKJLuuLAllisterEMLiuYJunLSSloopKWHardyABWeiLJiaWFantusIG 2014 The furan fatty acid metabolite CMPF is elevated in diabetes and induces beta cell dysfunction. Cell Metabolism 19 653666. (https://doi.org/10.1016/j.cmet.2014.03.008)

QuigleyJEElmarakbyAAKnightSFManhianiMMSteppDWOlearzcykJJImigJD 2009 Obesity induced renal oxidative stress contributes to renal injury in salt-sensitive hypertension. Clinical and Experimental Pharmacology and Physiology 36 724728. (https://doi.org/10.1111/j.1440-1681.2009.05139.x)

SharmaKKarlBMathewAVGangoitiJAWasselCLSaitoRPuMSharmaSYouYHWangL 2013 Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. Journal of the American Society of Nephrology 24 19011912. (https://doi.org/10.1681/ASN.2013020126)

SrinivasanKViswanadBAsratLKaulCLRamaraoP 2005 Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacological Research 52 313320. (https://doi.org/10.1016/j.phrs.2005.05.004)

StefanssonVTScheiJJenssenTGMelsomTEriksenBO 2016 Central obesity associates with renal hyperfiltration in the non-diabetic general population: a cross-sectional study. BMC Nephrology 17 172. (https://doi.org/10.1186/s12882-016-0386-4)

TunapongWApaijaiNYasomSTanajakPWanchaiKChunchaiTKerdphooSEaimworawuthikulSThiennimitrPPongchaidechaA 2017 Chronic treatment with prebiotics, probiotics and synbiotics attenuated cardiac dysfunction by improving cardiac mitochondrial dysfunction in male obese insulin-resistant rats. European Journal of Nutrition [epub]. (https://doi.org/10.1007/s00394-017-1482-3)

VallonVEralySARaoSRGerasimovaMRoseMNagleMAnzaiNSmithTSharmaKNigamSK 2012 A role for the organic anion transporter OAT3 in renal creatinine secretion in mice. American Journal of Physiology: Renal Physiology 302 F1293F1299. (https://doi.org/10.1152/ajprenal.00013.2012)

WangLSweetDH 2013 Renal organic anion transporters (SLC22 family): expression, regulation, roles in toxicity, and impact on injury and disease. AAPS Journal 15 5369. (https://doi.org/10.1208/s12248-012-9413-y)

WangYChenXSongYCaballeroBCheskinLJ 2008 Association between obesity and kidney disease: a systematic review and meta-analysis. Kidney International 73 1933. (https://doi.org/10.1038/sj.ki.5002586)

WangJCaoYWangCSunB 2011 Wheat bran xylooligosaccharides improve blood lipid metabolism andantioxidant status in rats fed a high-fat diet. Carbohydrate Polymers 86 11921197. (https://doi.org/10.1016/j.carbpol.2011.06.014)

WangXWuHChenHLiuRLiuJZhangTYuWHaiC 2012 Does insulin bolster antioxidant defenses via the extracellular signal-regulated kinases-protein kinase B-nuclear factor erythroid 2 p45-related factor 2 pathway? Antioxidants and Redox Signaling 16 10611070. (https://doi.org/10.1089/ars.2011.4460)

WangWJChengMHSunMFHsuSFWengCS 2014 Indoxyl sulfate induces renin release and apoptosis of kidney mesangial cells. Journal of Toxicological Sciences 39 637643. (http://doi.org/10.2131/jts.39.637)

WatanabeHMiyamotoYHondaDTanakaHWuQEndoMNoguchiTKadowakiDIshimaYKotaniS 2013 p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney International 83 582592. (https://doi.org/10.1038/ki.2012.448)

WuWBushKTNigamSK 2017 Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes. Scientific Reports 7 4939. (https://doi.org/10.1038/s41598-017-04949-2)

ZhangHWangJLiuYSunB 2015 Wheat bran feruloyl oligosaccharides modulate the phase II detoxifying/antioxidant enzymes via Nrf2 signaling. International Journal of Biological Macromolecules 74 150154. (https://doi.org/10.1016/j.ijbiomac.2014.12.011)

ZhuQSchererPE 2017 Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nature Reviews Nephrology 14 105120. (https://doi.org/10.1038/nrneph.2017.157)

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