Generic placeholder image

Current Diabetes Reviews

Editor-in-Chief

ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Review Article

Lipids: A Major Culprit in Diabetic Nephropathy

Author(s): Ankita Beniwal, Jasmine Chaudhary Jain and Akash Jain*

Volume 20, Issue 8, 2024

Published on: 24 November, 2023

Article ID: e241123223804 Pages: 10

DOI: 10.2174/0115733998259273231101052549

Price: $65

Abstract

The pathophysiology of diabetic nephropathy (DN) is too complex and involves a variety of pathways and mediators. Hyperglycaemia and dyslipidemia are identified as major risk factors for diabetic nephropathy. Various studies revealed the fact that dyslipidemia is a major contributor to the process of diabetic nephropathy. Dyslipidemia refers to abnormal lipid levels. Lipids like LDL, free fatty acids, abnormal lipoproteins, ceramides, etc., are unsafe for kidneys. They target proximal tubular epithelial cells, podocytes, and tubulointerstitial tissues through biochemical changes, especially by enhancing the release of reactive oxygen species (ROS) and lipid peroxidation, endorsing tissue inflammation and mitochondrial damage, which give rise to nephropathy. Major lipid targets identified are SREBP1, LXR, FXR PPAR, CD-36, PKc, AGE/RAGE pathway, and ferroptosis. The drug acting on these targets has shown improvement in DN patients. Various preclinical and clinical studies support the fact that hyperlipidemic agents are promising targets for DN. Therefore, in conjunction with other standard therapies, drugs acting on dyslipidemia can be added as a part of the regimen in order to prevent the incidence of ESRD and CVD.

[1]
Vodošek Hojs N, Bevc S, Ekart R, Hojs R. Oxidative stress markers in chronic kidney disease with emphasis on diabetic nephropathy. Antioxidants 2020; 9(10): 925.
[http://dx.doi.org/10.3390/antiox9100925] [PMID: 32992565]
[2]
Chen S, Tseng CH. Dyslipidemia, kidney disease, and cardiovascular disease in diabetic patients. Rev Diabet Stud 2013; 10(2-3): 88-100.
[http://dx.doi.org/10.1900/RDS.2013.10.88] [PMID: 24380085]
[3]
Mitrofanova A, Burke G, Merscher S, Fornoni A. New insights into renal lipid dysmetabolism in diabetic kidney disease. World J Diabetes 2021; 12(5): 524-40.
[http://dx.doi.org/10.4239/wjd.v12.i5.524] [PMID: 33995842]
[4]
Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80(6): 572-86.
[http://dx.doi.org/10.1038/ki.2011.223] [PMID: 21750584]
[5]
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351(13): 1296-305.
[http://dx.doi.org/10.1056/NEJMoa041031] [PMID: 15385656]
[6]
Keane WF, Tomassini JE, Neff DR. Lipid abnormalities in patients with chronic kidney disease: Implications for the pathophysiology of atherosclerosis. J Atheroscler Thromb 2013; 20(2): 123-33.
[http://dx.doi.org/10.5551/jat.12849] [PMID: 23095239]
[7]
Shoji T, Abe T, Matsuo H, et al. Chronic kidney disease, dyslipidemia, and atherosclerosis. J Atheroscler Thromb 2012; 19(4): 299-315.
[http://dx.doi.org/10.5551/jat.10454] [PMID: 22166970]
[8]
Wanner C, Tonelli M. Kidney disease: Improving global outcomes lipid guideline development work group members KDIGO clinical practice guideline for lipid management in CKD: Summary of recommendation statements and clinical approach to the patient. Kidney Int 2014; 85: 1303-9.
[9]
Singh AK, Farag YMK, Mittal BV, et al. Epidemiology and risk factors of chronic kidney disease in India-results from the SEEK (Screening and Early Evaluation of Kidney Disease) study. BMC Nephrol 2013; 14(1): 114.
[http://dx.doi.org/10.1186/1471-2369-14-114] [PMID: 23714169]
[10]
Umanath K, Lewis JB. Update on diabetic nephropathy: Core curriculum 2018. Am J Kidney Dis 2018; 71(6): 884-95.
[http://dx.doi.org/10.1053/j.ajkd.2017.10.026] [PMID: 29398179]
[11]
Su W, Cao R, He YC, Guan YF, Ruan XZ. Crosstalk of hyperglycemia and dyslipidemia in diabetic kidney disease. Kidney Dis 2017; 3(4): 171-80.
[http://dx.doi.org/10.1159/000479874] [PMID: 29344511]
[12]
Srivastava SP, Shi S, Koya D, Kanasaki K. Lipid mediators in diabetic nephropathy. Fibrogenesis Tissue Repair 2014; 7(1): 12.
[http://dx.doi.org/10.1186/1755-1536-7-12] [PMID: 25206927]
[13]
Alice CP, Heather LM, Tamberly P. Lipid types and structures. Nutrition: science and everyday application. (2nd Ed..). powerpress 2020; pp. 270-93.
[14]
Feingold KR. Introduction to lipids and lipoproteins. In: Feingold KR, Anawalt B, Blackman MR, Eds.
[15]
Gai Z, Wang T, Visentin M, Kullak-Ublick G, Fu X, Wang Z. Lipid accumulation and chronic kidney disease. Nutrients 2019; 11(4): 722.
[http://dx.doi.org/10.3390/nu11040722] [PMID: 30925738]
[16]
Pappan N, Rehman A. Dyslipidemia. StatPearls. Treasure island FL: StatPearls publishing 2023. Available from: http://www.ncbi.nlm.nih.gov/books/NBK560891/
[17]
Njeim R, Alkhansa S, Fornoni A. Unraveling the crosstalk between lipids and NADPH oxidases in diabetic kidney disease. Pharmaceutics 2023; 15(5): 1360.
[http://dx.doi.org/10.3390/pharmaceutics15051360] [PMID: 37242602]
[18]
Murea M, Freedman BI, Parks JS, Antinozzi PA, Elbein SC, Ma L. Lipotoxicity in diabetic nephropathy: the potential role of fatty acid oxidation. Clin J Am Soc Nephrol 2010; 5(12): 2373-9.
[http://dx.doi.org/10.2215/CJN.08160910] [PMID: 21051750]
[19]
Chen HC, Guh JY, Chang JM, Hsieh MC, Shin SJ, Lai YH. Role of lipid control in diabetic nephropathy. Kidney Int 2005; 67(94): S60-2.
[http://dx.doi.org/10.1111/j.1523-1755.2005.09415.x] [PMID: 15752242]
[20]
Bobulescu IA. Renal lipid metabolism and lipotoxicity. Curr Opin Nephrol Hypertens 2010; 19(4): 393-402.
[http://dx.doi.org/10.1097/MNH.0b013e32833aa4ac] [PMID: 20489613]
[21]
Ng KF, Aung HH, Rutledge JC. Role of triglyceride-rich lipoproteins in renal injury. Contrib Nephrol 2011; 170: 165-71.
[http://dx.doi.org/10.1159/000325654] [PMID: 21659769]
[22]
Park CW, Zhang Y, Zhang X, et al. PPARα agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int 2006; 69(9): 1511-7.
[http://dx.doi.org/10.1038/sj.ki.5000209] [PMID: 16672921]
[23]
Trevisan R, Dodesini AR, Lepore G. Lipids and renal disease. J Am Soc Nephrol 2006; 17 (suppl_2): S145-7.
[http://dx.doi.org/10.1681/ASN.2005121320] [PMID: 16565240]
[24]
Ge M, Merscher S, Fornoni A. Use of lipid-modifying agents for the treatment of glomerular diseases. J Pers Med 2021; 11(8): 820.
[http://dx.doi.org/10.3390/jpm11080820] [PMID: 34442464]
[25]
Kachhawa K, Agrawal D, Rath B, Kumar S. Association of lipid abnormalities and oxidative stress with diabetic nephropathy. Journal of Integrative Nephrology and Andrology 2017; 4(1): 3.
[http://dx.doi.org/10.4103/jina.jina_1_17]
[26]
Nakamichi R, Hayashi K, Itoh H. Effects of high glucose and lipotoxicity on diabetic podocytes. Nutrients 2021; 13(1): 241.
[http://dx.doi.org/10.3390/nu13010241]
[27]
Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res 2014; 55(3): 561-72.
[http://dx.doi.org/10.1194/jlr.P040501] [PMID: 24371263]
[28]
Cheng CF, Chen HH, Lin H. Role of PPAR α and its agonist in renal diseases. PPAR Res 2010; 2010: 1-6.
[http://dx.doi.org/10.1155/2010/345098] [PMID: 21076544]
[29]
Kawanami D, Matoba K, Utsunomiya K. Dyslipidemia in diabetic nephropathy. Renal Replacement Therapy 2016; 2(1): 16.
[http://dx.doi.org/10.1186/s41100-016-0028-0]
[30]
Stadler K, Goldberg IJ, Susztak K. The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease. Curr Diab Rep 2015; 15(7): 40.
[http://dx.doi.org/10.1007/s11892-015-0611-8]
[31]
Menne J, Meier M, Park JK, Haller H. Inhibition of protein kinase C in diabetic nephropathy-where do we stand? Nephrol Dial Transplant 2009; 24(7): 2021-3.
[http://dx.doi.org/10.1093/ndt/gfp150] [PMID: 19349294]
[32]
Sun L, Halaihel N, Zhang W, Rogers T, Levi M. Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus. J Biol Chem 2002; 277(21): 18919-27.
[http://dx.doi.org/10.1074/jbc.M110650200] [PMID: 11875060]
[33]
Yap F, Craddock L, Yang J. Mechanism of AMPK suppression of LXR-dependent Srebp-1c transcription. Int J Biol Sci 2011; 7(5): 645-50.
[http://dx.doi.org/10.7150/ijbs.7.645] [PMID: 21647332]
[34]
Eiselein L, Wilson DW, Lamé MW, Rutledge JC. Lipolysis products from triglyceride-rich lipoproteins increase endothelial permeability, perturb zonula occludens-1 and F-actin, and induce apoptosis. Am J Physiol Heart Circ Physiol 2007; 292(6): H2745-53.
[http://dx.doi.org/10.1152/ajpheart.00686.2006] [PMID: 17259442]
[35]
Iacobini C, Menini S, Ricci C, et al. Advanced lipoxidation end‐products mediate lipid‐induced glomerular injury: Role of receptor‐mediated mechanisms. J Pathol 2009; 218(3): 360-9.
[http://dx.doi.org/10.1002/path.2536] [PMID: 19334049]
[36]
Huang YC, Chen SY, Liu SP, et al. Cholesteryl ester transfer protein genetic variants associated with risk for Type 2 Diabetes and diabetic kidney disease in taiwanese population. Genes 2019; 10(10): 782.
[http://dx.doi.org/10.3390/genes10100782] [PMID: 31597401]
[37]
Chen Y, Dong J, Zhang X, et al. Evacetrapib reduces preβ-1 HDL in patients with atherosclerotic cardiovascular disease or diabetes. Atherosclerosis 2019; 285: 147-52.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.04.211] [PMID: 31054484]
[38]
Bigagli E, Lodovici M. Circulating oxidative stress biomarkers in clinical studies on type 2 diabetes and its complications. Oxid Med Cell Longev 2019; 2019: 1-17.
[http://dx.doi.org/10.1155/2019/5953685] [PMID: 31214280]
[39]
Kim S, Kang SW, Joo J, et al. Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death Dis 2021; 12(2): 160.
[http://dx.doi.org/10.1038/s41419-021-03452-x] [PMID: 33558472]
[40]
Wang Y, Bi R, Quan F, et al. Ferroptosis involves in renal tubular cell death in diabetic nephropathy. Eur J Pharmacol 2020; 888: 173574.
[http://dx.doi.org/10.1016/j.ejphar.2020.173574] [PMID: 32976829]
[41]
Mychaleckyj JC, Craven T, Nayak U, et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care 2012; 35(5): 1008-14.
[http://dx.doi.org/10.2337/dc11-1811] [PMID: 22432114]
[42]
Baigent C, Landray M, Leaper C, et al. First United Kingdom Heart and Renal Protection (UK-HARP-I) study: Biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. Am J Kidney Dis 2005; 45(3): 473-84.
[http://dx.doi.org/10.1053/j.ajkd.2004.11.015] [PMID: 15754269]
[43]
Jun M, Zhu B, Tonelli M, et al. Effects of fibrates in kidney disease: A systematic review and meta-analysis. J Am Coll Cardiol 2012; 60(20): 2061-71.
[http://dx.doi.org/10.1016/j.jacc.2012.07.049] [PMID: 23083786]
[44]
Udani SM, Bakris GL. Do fibrates truly preserve kidney function? Nat Rev Endocrinol 2011; 7(3): 130-1.
[http://dx.doi.org/10.1038/nrendo.2011.14] [PMID: 21301489]
[45]
Pedigo CE, Ducasa GM, Leclercq F, et al. Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. J Clin Invest 2016; 126(9): 3336-50.
[http://dx.doi.org/10.1172/JCI85939] [PMID: 27482889]
[46]
Kim MY, Lim JH, Youn HH, et al. Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice. Diabetologia 2013; 56(1): 204-17.
[http://dx.doi.org/10.1007/s00125-012-2747-2] [PMID: 23090186]
[47]
Soetikno V, Sari FR, Sukumaran V, et al. Curcumin decreases renal triglyceride accumulation through AMPK–SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats. J Nutr Biochem 2013; 24(5): 796-802.
[http://dx.doi.org/10.1016/j.jnutbio.2012.04.013] [PMID: 22898567]
[48]
Gai Z, Gui T, Hiller C, Kullak-Ublick GA, Farnesoid X. Farnesoid X receptor protects against kidney injury in uninephrectomized obese mice. J Biol Chem 2016; 291(5): 2397-411.
[http://dx.doi.org/10.1074/jbc.M115.694323] [PMID: 26655953]
[49]
G B, v G, T S, A S MK, C HK, G SK. Hypolipidemic and antioxidant properties of oryzanol concentrate in reducing diabetic nephropathy via SREBP1 downregulation rather than β-Oxidation. Mol Nutr Food Res 2018; 62(8): e1700511.
[http://dx.doi.org/10.1002/mnfr.201700511] [PMID: 29469229]
[50]
Kim JE, Lee MH, Nam DH, et al. Celastrol, an NF-κB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice. PLoS One 2013; 8(4): e62068.
[http://dx.doi.org/10.1371/journal.pone.0062068] [PMID: 23637966]
[51]
Zhang C, Shao M, Yang H, et al. Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. PLoS One 2013; 8(12): e82275.
[http://dx.doi.org/10.1371/journal.pone.0082275] [PMID: 24349242]
[52]
Qin X, Zhao Y, Gong J, et al. Berberine protects glomerular podocytes via inhibiting drp1-mediated mitochondrial fission and dysfunction. Theranostics 2019; 9(6): 1698-713.
[http://dx.doi.org/10.7150/thno.30640] [PMID: 31037132]
[53]
Jayachandran M, Wu Z, Ganesan K, Khalid S, Chung SM, Xu B. Isoquercetin upregulates antioxidant genes, suppresses inflammatory cytokines and regulates AMPK pathway in streptozotocin-induced diabetic rats. Chem Biol Interact 2019; 303: 62-9.
[http://dx.doi.org/10.1016/j.cbi.2019.02.017] [PMID: 30817903]
[54]
Jiang X, Yu J, Wang X, Ge J, Li N. Quercetin improves lipid metabolism via SCAP-SREBP2-LDLr signaling pathway in early stage diabetic nephropathy. Diabetes Metab Syndr Obes 2019; 12: 827-39.
[http://dx.doi.org/10.2147/DMSO.S195456] [PMID: 31239739]
[55]
Wang XX, Levi J, Luo Y, et al. SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice. J Biol Chem 2017; 292(13): 5335-48.
[http://dx.doi.org/10.1074/jbc.M117.779520] [PMID: 28196866]
[56]
Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care 2005; 28(1): 164-76.
[http://dx.doi.org/10.2337/diacare.28.1.164] [PMID: 15616252]
[57]
Vlassara H, Uribarri J, Cai W, et al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol 2012; 7(6): 934-42.
[http://dx.doi.org/10.2215/CJN.12891211] [PMID: 22461535]
[58]
Shan D, Wu HM, Yuan QY, Li J, Zhou RL, Liu GJ. Pentoxifylline for diabetic kidney disease. Cochrane Libr 2012; (2): CD006800.
[http://dx.doi.org/10.1002/14651858.CD006800.pub2] [PMID: 22336824]
[59]
Tang WH, Lin FH, Lee CH, et al. Cilostazol effectively attenuates deterioration of albuminuria in patients with type 2 diabetes: A randomized, placebo-controlled trial. Endocrine 2014; 45(2): 293-301.
[http://dx.doi.org/10.1007/s12020-013-0002-3] [PMID: 23775007]
[60]
Scheele W, Diamond S, Gale J, et al. Phosphodiesterase Type 5 inhibition reduces albuminuria in subjects with overt diabetic nephropathy. J Am Soc Nephrol 2016; 27(11): 3459-68.
[http://dx.doi.org/10.1681/ASN.2015050473] [PMID: 27113485]
[61]
Sharma K, Ix JH, Mathew AV, et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol 2011; 22(6): 1144-51.
[http://dx.doi.org/10.1681/ASN.2010101049] [PMID: 21511828]
[62]
Wang J, Xiang H, Lu Y, Wu T, Ji G. New progress in drugs treatment of diabetic kidney disease. Biomed Pharmacother 2021; 141: 111918.
[http://dx.doi.org/10.1016/j.biopha.2021.111918] [PMID: 34328095]
[63]
Linkermann A, Skouta R, Himmerkus N, et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci USA 2014; 111(47): 16836-41.
[http://dx.doi.org/10.1073/pnas.1415518111] [PMID: 25385600]
[64]
Moriwaki Y, Inokuchi T, Yamamoto A, et al. Effect of TNF-α inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol 2007; 44(4): 215-8.
[http://dx.doi.org/10.1007/s00592-007-0007-6] [PMID: 17767370]
[65]
Wang Y, Yu B, Wang L, et al. Pioglitazone ameliorates glomerular NLRP3 inflammasome activation in apolipoprotein E knockout mice with diabetes mellitus. PLoS One 2017; 12(7): e0181248.
[http://dx.doi.org/10.1371/journal.pone.0181248] [PMID: 28708885]
[66]
Lin YC, Chang YH, Yang SY, Wu KD, Chu TS. Update of pathophysiology and management of diabetic kidney disease. J Formos Med Assoc 2018; 117(8): 662-75.
[http://dx.doi.org/10.1016/j.jfma.2018.02.007] [PMID: 29486908]
[67]
Bulbul MC, Dagel T, Afsar B, et al. Disorders of lipid metabolism in chronic kidney disease. Blood Purif 2018; 46(2): 144-52.
[http://dx.doi.org/10.1159/000488816] [PMID: 29705798]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy