肥胖相关性肾病的研究进展
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摘要
随着肥胖的全球流行,肥胖相关性肾病(ORG)发生率明显增高。ORG临床表现为不同程度的蛋白尿,少数患者进展至慢性肾功能不全甚至终末期肾病。ORG的发生与血流动力学异常、肾素-血管紧张素-醛固酮系统激活、胰岛素抵抗、脂代谢紊乱、脂肪细胞因子紊乱、微炎症作用等有关。其治疗方案多样,包括减轻体质量、降压、调节代谢等。本文对ORG的发病机制及治疗新进展,包括靶向治疗做一综述。
The increase of obesity-related glomerulopathy(ORG) parallels to the global epidemic of obesity. And the clinical feature of ORG shows different degrees of proteinuria,with some patients reaching end-stage renal failure. However,the pathogenesis,including hemodynamic abnormalities,renin-angiotensin-aldosterone system activation,insulin resistance,lipid metabolism disorder,adipose factor disorder,inflammation,is not clear. Its treatments include weight loss,blood pressure reduction,metabolic regulation and others. In this article,we reviewed the new progress in pathogenesis and therapies of ORG,including the targeted therapy.
The increase of obesity-related glomerulopathy(ORG) parallels to the global epidemic of obesity. And the clinical feature of ORG shows different degrees of proteinuria,with some patients reaching end-stage renal failure. However,the pathogenesis,including hemodynamic abnormalities,renin-angiotensin-aldosterone system activation,insulin resistance,lipid metabolism disorder,adipose factor disorder,inflammation,is not clear. Its treatments include weight loss,blood pressure reduction,metabolic regulation and others. In this article,we reviewed the new progress in pathogenesis and therapies of ORG,including the targeted therapy.
引文
[1]GBD 2013 Risk Factors Collaborators,FOROUZANFAR M H,ALEXANDER L,et al.Global,regional,and national comparative risk assessment of 79 behavioural,environmental and occupational,and metabolic risks or clusters of risks in 188 countries,1990—2013:a systematic analysis for the Global Burden of Disease Study2013[J].Lancet,2015,386(10010):2287-2323.DOI:10.1016/S0140-6736(15)00128-2.
[2]KANASAKI K,KOYA D.Biology of obesity:lessons from animal models of obesity[J].J Biomed Biotechnol,2011,2011:197636.DOI:10.1155/2011/197636.
[3]GUEBRE-EGZIABHER F,ALIX P M,KOPPE L,et al.Ectopic lipid accumulation:a potential cause for metabolic disturbances and a contributor to the alteration of kidney function[J].Biochimie,2013,95(11):1971-1979.DOI:10.1016/j.biochi.2013.07.017.
[4]CHAGNAC A,HERMAN M,ZINGERMAN B,et al.Obesityinducedglomerularhyperfiltration:itsinvolvementinthe pathogenesis of tubular sodium reabsorption[J].Nephrol Dial Transplant,2008,23(12):3946-3952.DOI:10.1093/ndt/gfn379.
[5]OGNA A,FORNI OGNA V,BOCHUD M,et al.Association between obesity and glomerular hyperfiltration:the confounding effect of smoking and sodium and protein intakes[J].Eur J Nutr,2016,55(3):1089-1097.DOI:10.1007/s00394-015-0923-0.
[6]KRIZ W,LEMLEY K V.A potential role for mechanical forces in the detachment of podocytes and the progression of CKD[J].JAmSocNephrol,2015,26(2):258-269.DOI:10.1681/ASN.2014030278.
[7]ACHARD V,BOULLU-CIOCCA S,DESBRIERE R,et al.Renin receptor expression in human adipose tissue[J].Am J Physiol Regul Integr Comp Physiol,2007,292(1):R274-282.DOI:10.1152/ajpregu.00439.2005.
[8]KAWARAZAKI W,NAGASE M,YOSHIDA S,et al.AngiotensinⅡ-and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation[J].J Am Soc Nephrol,2012,23(6):997-1007.DOI:10.1681/ASN.2011070734.
[9]CANAUD G,BIENAIMéF,VIAU A,et al.AKT2 is essential to maintain podocyte viability and function during chronic kidney disease[J].Nat Med,2013,19(10):1288-1296.DOI:10.1038/nm.3313.
[10]CHEN H M,CHEN Y,ZHANG Y D,et al.Evaluation of metabolic risk marker in obesity-related glomerulopathy[J].JRenNutr,2011,21(4):309-315.DOI:10.1053/j.jrn.2010.06.019.
[11]ELSAYED E F,SARNAK M J,TIGHIOUART H,et al.Waistto-hip ratio,body mass index,and subsequent kidney disease and death[J].Am J Kidney Dis,2008,52(1):29-38.DOI:10.1053/j.ajkd.2008.02.363.
[12]WAGNER R,MACHANN J,LEHMANN R,et al.Exerciseinduced albuminuria is associated with perivascular renal sinus fat in individuals at increased risk of type 2 diabetes[J].Di a b e t ol o g i a,20 1 2,55(7):2 054-20 58.DOI:10.1007/s00125-012-2551-z.
[13]CHUNG J J,HUBER T B,G?DEL M,et al.Albumin-associated free fatty acids induce macropinocytosis in podocytes[J].J Clin Invest,2015,125(6):2307-2316.DOI:10.1172/JCI79641.
[14]SZETO H H,LIU S,SOONG Y,et al.Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury[J].Kidney Int,2016,90(5):997-1011.DOI:10.1016/j.kint.2016.06.013.
[15]GONZáLEZ-PéRIZ A,CLàRIA J.Resolution of adipose tissue inflammation[J].Scientific World Journal,2010,10:832-856.DOI:10.1100/tsw.2010.77.
[16]NASRALLAH M P,ZIYADEH F N.Overview of the physiology and pathophysiology of leptin with special emphasis on its role in the kidney[J].Semin Nephrol,2013,33(1):54-65.DOI:10.1016/j.semnephrol.2012.12.005.
[17]TANG J,YAN H,ZHUANG S.Inflammation and oxidative stress in obesity-related glomerulopathy[J].Int J Nephrol,2012,2012:608397.DOI:10.1155/2012/608397.
[18]SHARMAK,RAMACHANDRARAOS,QIUG,etal.Adiponectin regulates albuminuria and podocyte function in mice[J].J Clin Invest,2008,118(5):1645-1656.DOI:10.1172/JCI32691.
[19]KIM J E,LEE M H,NAM D H,et al.Celastrol,an NF-κB inhibitor,improves insulin resistance and attenuates renal injury in db/db mice[J].PLoS One,2013,8(4):e62068.DOI:10.1371/journal.pone.0062068.
[20]MANABE I.Chronic inflammation links cardiovascular,metabolic and renal diseases[J].Circ J,2011,75(12):2739-2748.DOI:10.1253/circj.CJ-11-1184.
[21]SHEN W W,CHEN H M,CHEN H,et al.Obesity-related glomerulopathy:bodymassindexandproteinuria[J].Clin J Am Soc Nephrol,2010,5(8):1401-1409.DOI:10.2215/CJN.01370210.
[22]SERRA A,ESTEVE A,NAVARRO-DíAZ M,et al.Long-term normal renal function after drastic weight reduction in patients with obesity-related glomerulopathy[J].Obes Facts,2015,8(3):188-199.DOI:10.1159/000431027.
[23]CHAN G C,LAM B,YAP D Y,et al.Proteinuria is associated with sleep apnea in chronic kidney disease[J].Nephrol Dial Transplant,2016,31(5):772-779.DOI:10.1093/ndt/gfv306.
[24]DASKALOPOULOU E G,LIAVVAS C,NAKAS C T,et al.Obstructive sleep apnoea syndrome promotes reversal albuminuria during sleep[J].Sleep Breath,2011,15(3):589-597.DOI:10.1007/s11325-010-0408-6.
[25]KAMBHAM N,MARKOWITZ G S,VALERI A M,et al.Obesity-related glomerulopathy:an emerging epidemic[J].Kidney Int,2001,59(4):1498-1509.DOI:10.1046/j.1523-1755.2001.0590041498.x.
[26]PRAGA M,HERNáNDEZ E,MORALES E,et al.Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis[J].Nephrol Dial Transplant,2001,16(9):1790-1798.
[27]BOMBACK A S,MUSKALA P,BALD E,et al.Low-dose spironolactone,added to long-term ACE inhibitor therapy,reduces blood pressure and urinary albumin excretion in obese patients with hypertensive target organ damage[J].Clin Nephrol,2009,72(6):449-456.DOI:10.5414/CNP72449.
[28]HOUFF,XIED,ZHANGX,etal.Renoprotectionof optimal antiproteinuric doses(ROAD)study:a randomized controlled study of benazepril and losartan in chronic renal insufficiency[J].J Am Soc Nephrol,2007,18(6):1889-1898.DOI:10.1681/ASN.2006121372.
[29]NISTALA R,HABIBI J,AROOR A,et al.DPP4 inhibition attenuates filtration barrier injury and oxidant stress in the zucker obese rat[J].Obesity(Silver Spring),2014,22(10):2172-2179.DOI:10.1002/oby.20833.
[30]JAIKUMKAO K,PONGCHAIDECHA A,CHUEAKULA N,et al.Renal outcomes with sodium glucose cotransporter 2(SGLT2)inhibitor,dapagliflozin,in obese insulin-resistant model[J].Biochim Biophys Acta Mol Basis Dis,2018,1864(6 Pt A):2021-2033.DOI:10.1016/j.bbadis.2018.03.017.
[31]WANGC,LIL,LIUS,etal.GLP-1receptoragonist ameliorates obesity-induced chronic kidney injury via restoring renal metabolism homeostasis[J].PLoS One,2018,13(3):e0193473.DOI:10.1371/journal.pone.0193473.
[32]LUO M,LUO P,ZHANG Z,et al.Zinc delays the progression of obesity-related glomerulopathy in mice via down-regulating P38MAPK-mediated inflammation[J].Obesity(Silver Spring),2016,24(6):1244-1256.DOI:10.1002/oby.21463.
[33]LIU B L,CHEN Y P,CHENG H,et al.The protective effects of curcumin on obesity-related glomerulopathy are associated withinhibitionofWnt/β-cateninsignalingactivationin podocytes[J].Evid Based Complement Alternat Med,2015,2015:827472.DOI:10.1155/2015/827472.
[34]FANG Q,DENG L,WANG L,et al.Inhibition of mitogenactivated protein kinases/nuclear factorκB-dependent inflammation by a novel chalcone protects the kidney from high fat diet-induced injuries in mice[J].J Pharmacol Exp Ther,2015,355(2):235-246.DOI:10.1124/jpet.115.226860.
[35]WANG X X,EDELSTEIN M H,GAFTER U,et al.G Proteincoupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes[J].J Am Soc Nephrol,2016,27(5):1362-1378.DOI:10.1681/ASN.2014121271.
[36]GUO H,WANG B,LI H,et al.Glucagon-like peptide-1 analog prevents obesity-related glomerulopathy by inhibiting excessive autophagy in podocytes[J].Am J Physiol Renal Physiol,2018,314(2):F181-189.DOI:10.1152/ajprenal.00302.2017.
[2]KANASAKI K,KOYA D.Biology of obesity:lessons from animal models of obesity[J].J Biomed Biotechnol,2011,2011:197636.DOI:10.1155/2011/197636.
[3]GUEBRE-EGZIABHER F,ALIX P M,KOPPE L,et al.Ectopic lipid accumulation:a potential cause for metabolic disturbances and a contributor to the alteration of kidney function[J].Biochimie,2013,95(11):1971-1979.DOI:10.1016/j.biochi.2013.07.017.
[4]CHAGNAC A,HERMAN M,ZINGERMAN B,et al.Obesityinducedglomerularhyperfiltration:itsinvolvementinthe pathogenesis of tubular sodium reabsorption[J].Nephrol Dial Transplant,2008,23(12):3946-3952.DOI:10.1093/ndt/gfn379.
[5]OGNA A,FORNI OGNA V,BOCHUD M,et al.Association between obesity and glomerular hyperfiltration:the confounding effect of smoking and sodium and protein intakes[J].Eur J Nutr,2016,55(3):1089-1097.DOI:10.1007/s00394-015-0923-0.
[6]KRIZ W,LEMLEY K V.A potential role for mechanical forces in the detachment of podocytes and the progression of CKD[J].JAmSocNephrol,2015,26(2):258-269.DOI:10.1681/ASN.2014030278.
[7]ACHARD V,BOULLU-CIOCCA S,DESBRIERE R,et al.Renin receptor expression in human adipose tissue[J].Am J Physiol Regul Integr Comp Physiol,2007,292(1):R274-282.DOI:10.1152/ajpregu.00439.2005.
[8]KAWARAZAKI W,NAGASE M,YOSHIDA S,et al.AngiotensinⅡ-and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation[J].J Am Soc Nephrol,2012,23(6):997-1007.DOI:10.1681/ASN.2011070734.
[9]CANAUD G,BIENAIMéF,VIAU A,et al.AKT2 is essential to maintain podocyte viability and function during chronic kidney disease[J].Nat Med,2013,19(10):1288-1296.DOI:10.1038/nm.3313.
[10]CHEN H M,CHEN Y,ZHANG Y D,et al.Evaluation of metabolic risk marker in obesity-related glomerulopathy[J].JRenNutr,2011,21(4):309-315.DOI:10.1053/j.jrn.2010.06.019.
[11]ELSAYED E F,SARNAK M J,TIGHIOUART H,et al.Waistto-hip ratio,body mass index,and subsequent kidney disease and death[J].Am J Kidney Dis,2008,52(1):29-38.DOI:10.1053/j.ajkd.2008.02.363.
[12]WAGNER R,MACHANN J,LEHMANN R,et al.Exerciseinduced albuminuria is associated with perivascular renal sinus fat in individuals at increased risk of type 2 diabetes[J].Di a b e t ol o g i a,20 1 2,55(7):2 054-20 58.DOI:10.1007/s00125-012-2551-z.
[13]CHUNG J J,HUBER T B,G?DEL M,et al.Albumin-associated free fatty acids induce macropinocytosis in podocytes[J].J Clin Invest,2015,125(6):2307-2316.DOI:10.1172/JCI79641.
[14]SZETO H H,LIU S,SOONG Y,et al.Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury[J].Kidney Int,2016,90(5):997-1011.DOI:10.1016/j.kint.2016.06.013.
[15]GONZáLEZ-PéRIZ A,CLàRIA J.Resolution of adipose tissue inflammation[J].Scientific World Journal,2010,10:832-856.DOI:10.1100/tsw.2010.77.
[16]NASRALLAH M P,ZIYADEH F N.Overview of the physiology and pathophysiology of leptin with special emphasis on its role in the kidney[J].Semin Nephrol,2013,33(1):54-65.DOI:10.1016/j.semnephrol.2012.12.005.
[17]TANG J,YAN H,ZHUANG S.Inflammation and oxidative stress in obesity-related glomerulopathy[J].Int J Nephrol,2012,2012:608397.DOI:10.1155/2012/608397.
[18]SHARMAK,RAMACHANDRARAOS,QIUG,etal.Adiponectin regulates albuminuria and podocyte function in mice[J].J Clin Invest,2008,118(5):1645-1656.DOI:10.1172/JCI32691.
[19]KIM J E,LEE M H,NAM D H,et al.Celastrol,an NF-κB inhibitor,improves insulin resistance and attenuates renal injury in db/db mice[J].PLoS One,2013,8(4):e62068.DOI:10.1371/journal.pone.0062068.
[20]MANABE I.Chronic inflammation links cardiovascular,metabolic and renal diseases[J].Circ J,2011,75(12):2739-2748.DOI:10.1253/circj.CJ-11-1184.
[21]SHEN W W,CHEN H M,CHEN H,et al.Obesity-related glomerulopathy:bodymassindexandproteinuria[J].Clin J Am Soc Nephrol,2010,5(8):1401-1409.DOI:10.2215/CJN.01370210.
[22]SERRA A,ESTEVE A,NAVARRO-DíAZ M,et al.Long-term normal renal function after drastic weight reduction in patients with obesity-related glomerulopathy[J].Obes Facts,2015,8(3):188-199.DOI:10.1159/000431027.
[23]CHAN G C,LAM B,YAP D Y,et al.Proteinuria is associated with sleep apnea in chronic kidney disease[J].Nephrol Dial Transplant,2016,31(5):772-779.DOI:10.1093/ndt/gfv306.
[24]DASKALOPOULOU E G,LIAVVAS C,NAKAS C T,et al.Obstructive sleep apnoea syndrome promotes reversal albuminuria during sleep[J].Sleep Breath,2011,15(3):589-597.DOI:10.1007/s11325-010-0408-6.
[25]KAMBHAM N,MARKOWITZ G S,VALERI A M,et al.Obesity-related glomerulopathy:an emerging epidemic[J].Kidney Int,2001,59(4):1498-1509.DOI:10.1046/j.1523-1755.2001.0590041498.x.
[26]PRAGA M,HERNáNDEZ E,MORALES E,et al.Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis[J].Nephrol Dial Transplant,2001,16(9):1790-1798.
[27]BOMBACK A S,MUSKALA P,BALD E,et al.Low-dose spironolactone,added to long-term ACE inhibitor therapy,reduces blood pressure and urinary albumin excretion in obese patients with hypertensive target organ damage[J].Clin Nephrol,2009,72(6):449-456.DOI:10.5414/CNP72449.
[28]HOUFF,XIED,ZHANGX,etal.Renoprotectionof optimal antiproteinuric doses(ROAD)study:a randomized controlled study of benazepril and losartan in chronic renal insufficiency[J].J Am Soc Nephrol,2007,18(6):1889-1898.DOI:10.1681/ASN.2006121372.
[29]NISTALA R,HABIBI J,AROOR A,et al.DPP4 inhibition attenuates filtration barrier injury and oxidant stress in the zucker obese rat[J].Obesity(Silver Spring),2014,22(10):2172-2179.DOI:10.1002/oby.20833.
[30]JAIKUMKAO K,PONGCHAIDECHA A,CHUEAKULA N,et al.Renal outcomes with sodium glucose cotransporter 2(SGLT2)inhibitor,dapagliflozin,in obese insulin-resistant model[J].Biochim Biophys Acta Mol Basis Dis,2018,1864(6 Pt A):2021-2033.DOI:10.1016/j.bbadis.2018.03.017.
[31]WANGC,LIL,LIUS,etal.GLP-1receptoragonist ameliorates obesity-induced chronic kidney injury via restoring renal metabolism homeostasis[J].PLoS One,2018,13(3):e0193473.DOI:10.1371/journal.pone.0193473.
[32]LUO M,LUO P,ZHANG Z,et al.Zinc delays the progression of obesity-related glomerulopathy in mice via down-regulating P38MAPK-mediated inflammation[J].Obesity(Silver Spring),2016,24(6):1244-1256.DOI:10.1002/oby.21463.
[33]LIU B L,CHEN Y P,CHENG H,et al.The protective effects of curcumin on obesity-related glomerulopathy are associated withinhibitionofWnt/β-cateninsignalingactivationin podocytes[J].Evid Based Complement Alternat Med,2015,2015:827472.DOI:10.1155/2015/827472.
[34]FANG Q,DENG L,WANG L,et al.Inhibition of mitogenactivated protein kinases/nuclear factorκB-dependent inflammation by a novel chalcone protects the kidney from high fat diet-induced injuries in mice[J].J Pharmacol Exp Ther,2015,355(2):235-246.DOI:10.1124/jpet.115.226860.
[35]WANG X X,EDELSTEIN M H,GAFTER U,et al.G Proteincoupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes[J].J Am Soc Nephrol,2016,27(5):1362-1378.DOI:10.1681/ASN.2014121271.
[36]GUO H,WANG B,LI H,et al.Glucagon-like peptide-1 analog prevents obesity-related glomerulopathy by inhibiting excessive autophagy in podocytes[J].Am J Physiol Renal Physiol,2018,314(2):F181-189.DOI:10.1152/ajprenal.00302.2017.