Podocyte lipotoxicity in diabetic kidney disease: mechanisms and targets

Abstract

Podocyte lipotoxicity is a fundamental pathogenic mechanism in diabetic kidney disease (DKD), driven by aberrant intracellular lipid accumulation that disrupts cellular integrity and function. This review systematically examines the molecular and metabolic underpinnings of this process, focusing on dysregulated cholesterol efflux, impaired fatty acid oxidation, altered sphingolipid metabolism, and defective lipid droplet homeostasis. These disturbances converge to induce mitochondrial dysfunction, endoplasmic reticulum stress, oxidative damage, and inflammatory activation, collectively leading to podocyte apoptosis and loss. Emerging evidence further illuminates the role of epigenetic regulators, transcriptional networks, and inter-organ signaling in modulating lipotoxic responses. Mechanistic insights into podocyte lipid metabolism provide a critical foundation for developing targeted therapeutic strategies to preserve podocyte function in DKD.

Keywords

Podocyte lipotoxicity / diabetic kidney disease / cholesterol metabolism / fatty acid oxidation / inflammation / therapeutic targets

References

[1] Zuo F,Xu X.CCDC92 deficiency ameliorates podocyte lipotoxicity in diabetic kidney disease.Metabolism2024;150:155724

[2] Brinkkoetter PT,Salou S.Anaerobic glycolysis maintains the glomerular filtration barrier independent of mitochondrial metabolism and dynamics.Cell Rep2019;27:1551-66.e5 PMCID:PMC6506687

[3] Nakamichi R,Itoh H.Effects of high glucose and lipotoxicity on diabetic podocytes.Nutrients2021;13:241 PMCID:PMC7830342

[4] Hu H,Ding G.Podocyte metabolic reprogramming and targeted therapy.J Am Soc Nephrol2026;37:619-33 PMCID:PMC12935371

[5] Zang N,Guo X.cGAS-STING activation contributes to podocyte injury in diabetic kidney disease.iScience2022;25:105145 PMCID:PMC9513272

[6] Choi SR,Kim MY.Adiponectin receptor agonist AdipoRon decreased ceramide, and lipotoxicity, and ameliorated diabetic nephropathy.Metabolism2018;85:348-60

[7] Wang J,Hu H.APT1-derived depalmitoylation of CD36 alleviates diabetes-induced lipotoxicity in podocytes.Int J Biol Sci2025;21:3852-66 PMCID:PMC12210380

[8] Chae SY,Park CW.Oxidative stress induced by lipotoxicity and renal hypoxia in diabetic kidney disease and possible therapeutic interventions: targeting the lipid metabolism and hypoxia.Antioxidants2023;12:2083 PMCID:PMC10740440

[9] Zuo FW,Wang MW.CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice.Acta Pharmacol Sin2024;45:1019-31 PMCID:PMC11053164

[10] Nishi H.Podocyte lipotoxicity in diabetic kidney disease.Kidney Int2019;96:809-12

[11] Liu X,Mallela SK.Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome.Kidney Int2020;98:1275-85 PMCID:PMC7606642

[12] Fornoni A.Lipid metabolism gets in a JAML during kidney disease.Cell Metab2020;32:903-5 PMCID:PMC7978490

[13] Hu H,Peng Z,Yang Q.Dapagliflozin attenuates diabetes-induced podocyte lipotoxicity via ERRα-Mediated lipid metabolism.Free Radic Biol Med2025;234:178-91

[14] Requena B,Lanzon B.Lipidomics unveils critical lipid pathway shifts in Alport syndrome.Kidney Int Rep2025;10:2805-20 PMCID:PMC12347953

[15] Hu Y,Kong J.DOT1L protects against podocyte injury in diabetic kidney disease through phospholipase C-like 1.Cell Commun Signal2024;22:519 PMCID:PMC11515305

[16] Lee E.Peroxidase expression is decreased by palmitate in cultured podocytes but increased in podocytes of advanced diabetic nephropathy.J Cell Physiol2018;233:9060-9 PMCID:PMC6686159

[17] Wu M,Zhang C.Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy.Metabolism2021;118:154748

[18] Kim Y,Kim MY.The adiponectin receptor agonist AdipoRon ameliorates diabetic nephropathy in a model of type 2 diabetes.J Am Soc Nephrol2018;29:1108-27 PMCID:PMC5875945

[19] Luo Z,Hu J.Interplay of lipid metabolism and inflammation in podocyte injury.Metabolism2024;150:155718

[20] Schelling JR.The contribution of lipotoxicity to diabetic kidney disease.Cells2022;11:3236 PMCID:PMC9601125

[21] Ryu JH,Merscher S.APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice.PLoS One2019;14:e0211559 PMCID:PMC6472726

[22] Ge M,Ducasa GM.APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis.Hum Mol Genet2021;30:182-97 PMCID:PMC8091039

[23] Fu Y,Wang M.Elevation of JAML promotes diabetic kidney disease by modulating podocyte lipid metabolism.Cell Metab2020;32:1052-62.e8

[24] Loreth D,Meyer-Schwesinger C.The life of a kidney podocyte.Acta Physiol2025;241:e70081 PMCID:PMC12284917

[25] Fukusumi Y,Yamagishi R.Nephrin-binding Ephrin-B1 at the slit diaphragm controls podocyte function through the JNK pathway.J Am Soc Nephrol2018;29:1462-74 PMCID:PMC5967778

[26] Chang K,Liu H.FTO aggravates podocyte injury and diabetic nephropathy progression via m6A-dependent stabilization of ACC1 mRNA and promoting fatty acid metabolism.Biochem Pharmacol2025;235:116819

[27] Kim JJ,Wilbon SS.Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome.EBioMedicine2021;63:103162 PMCID:PMC7750578

[28] Ge M,Kim JJ.Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome.Elife2023;12:e83353 PMCID:PMC10185338

[29] Cansby E,Gao L.Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease.JCI Insight2020;5:140483 PMCID:PMC7819747

[30] Zhang Y,Li C.Gandi capsule improved podocyte lipid metabolism of diabetic nephropathy mice through SIRT1/AMPK/HNF4A pathway.Oxid Med Cell Longev2022;2022:6275505 PMCID:PMC9038418

[31] Ito Y,Bettaieb A.Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury.Metabolism2017;76:56-69 PMCID:PMC5690491

[32] Sieber J.Free fatty acids and their metabolism affect function and survival of podocytes.Front Endocrinol2014;5:186 PMCID:PMC4209866

[33] Carrasco AG,Valverde ÁM.The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes.Biochim Biophys Acta Mol Cell Biol Lipids2023;1868:159329

[34] Lee ES,Kim HM.Dehydrozingerone inhibits renal lipotoxicity in high-fat diet-induced obese mice.J Cell Mol Med2021;25:8725-33 PMCID:PMC8435425

[35] Nosadini R.Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes.Nutr Metab Cardiovasc Dis2011;21:79-85

[36] Tanaka Y,Maeda S.Overexpression of acetyl CoA carboxylase β exacerbates podocyte injury in the kidney of streptozotocin-induced diabetic mice.Biochem Biophys Res Commun2018;495:1115-21

[37] Locatelli M,Corna D.Sirtuin 3 deficiency aggravates kidney disease in response to high-fat diet through lipotoxicity-induced mitochondrial damage.Int J Mol Sci2022;23:8345 PMCID:PMC9368634

[38] Nicholson RJ,Summers SA.Rotten to the cortex: ceramide-mediated lipotoxicity in diabetic kidney disease.Front Endocrinol2020;11:622692 PMCID:PMC7876379

[39] Kume S.Lipotoxicity, nutrient-sensing signals, and autophagy in diabetic nephropathy.JMA J2020;3:87-94 PMCID:PMC7590395

[40] Cassis P,Cerullo D.SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy.JCI Insight2018;3:98720 PMCID:PMC6129124

[41] Park HS,Kim MY.Resveratrol increases AdipoR1 and AdipoR2 expression in type 2 diabetic nephropathy.J Transl Med2016;14:176 PMCID:PMC4902973

[42] Opazo-Ríos L,Marín-Royo G.Lipotoxicity and diabetic nephropathy: novel mechanistic insights and therapeutic opportunities.Int J Mol Sci2020;21:2632 PMCID:PMC7177360

[43] Mitrofanova A,Ducasa GM.SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.Nat Commun2019;10:2692 PMCID:PMC6584700

[44] Lee E,Lee HS.Palmitate induces mitochondrial superoxide generation and activates AMPK in podocytes.J Cell Physiol2017;232:3209-17

[45] Orellana JM,Schulze F,Jehle AW.Fetuin-A aggravates lipotoxicity in podocytes via interleukin-1 signaling.Physiol Rep2017;5:e13287 PMCID:PMC5449566

[46] Wang Q,Zhang J.Faster lipid β-oxidation rate by acetyl-CoA carboxylase 2 inhibition alleviates high-glucose-induced insulin resistance via SIRT1/PGC-1α in human podocytes.J Biochem Mol Toxicol2021;35:e22797

[47] Teng B,Müller-Deile J.CIN85 deficiency prevents nephrin endocytosis and proteinuria in diabetes.Diabetes2016;65:3667-79 PMCID:PMC5314701

[48] Kruger C,Collier JJ,Salbaum JM.Lipid peroxidation regulates podocyte migration and cytoskeletal structure through redox sensitive RhoA signaling.Redox Biol2018;16:248-54 PMCID:PMC5854917

[49] Xin R,Wang Z.Apocynin inhibited NLRP3/XIAP signalling to alleviate renal fibrotic injury in rat diabetic nephropathy.Biomed Pharmacother2018;106:1325-31

[50] Ke G,Liao R.Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy.Kidney Int2021;100:377-90

[51] He JY,Chen BX.Ginsenoside Rb1 alleviates diabetic kidney podocyte injury by inhibiting aldose reductase activity.Acta Pharmacol Sin2022;43:342-53 PMCID:PMC8791932

[52] Cui Y,Bao Y,Hua Q.Zingerone attenuates diabetic nephropathy through inhibition of nicotinamide adenine dinucleotide phosphate oxidase 4.Biomed Pharmacother2018;99:422-30

[53] Stanigut AM,Pana C.Autophagy and mitophagy in diabetic kidney disease-a literature review.Int J Mol Sci2025;26:806 PMCID:PMC11766107

[54] Baechler BL,Quadrilatero J.Mitophagy regulates mitochondrial network signaling, oxidative stress, and apoptosis during myoblast differentiation.Autophagy2019;15:1606-19 PMCID:PMC6693454

[55] Martinez A,Valls C.c-Abl phosphorylates MFN2 to regulate mitochondrial morphology in cells under endoplasmic reticulum and oxidative stress, impacting cell survival and neurodegeneration.Antioxidants2023;12:2007 PMCID:PMC10669615

[56] Ni L.The mitochondrial-associated endoplasmic reticulum membrane and its role in diabetic nephropathy.Oxid Med Cell Longev2021;2021:8054817 PMCID:PMC8589504

[57] Xue H,Luo Y.Salidroside stimulates the Sirt1/PGC-1α axis and ameliorates diabetic nephropathy in mice.Phytomedicine2019;54:240-7

[58] Wang X,Li Y,Xu G.Epigenetics and endoplasmic reticulum in podocytopathy during diabetic nephropathy progression.Front Immunol2022;13:1090989 PMCID:PMC9813850

[59] Wang M,Tang Z.Natural products derived from traditional Chinese medicines targeting ER stress for the treatment of kidney diseases.Ren Fail2024;46:2396446 PMCID:PMC11360642

[60] Liu Q,Tong Y.Renal lipotoxicity in diabetic and obesity-associated kidney diseases: Molecular mechanisms and therapeutic targeting.Diabetes Obes Metab2026;28:60-82

[61] Cha JJ,Lee MH.Renal protective effects of toll-like receptor 4 signaling blockade in type 2 diabetic mice.Endocrinology2013;154:2144-55

[62] Li Z,Lin J.Podocyte TLR4 deletion alleviates diabetic kidney disease through prohibiting PKCδ/SHP-1-dependent ER stress and relieving podocyte damage and inflammation.J Adv Res2026;82:845-62 PMCID:PMC13001067

[63] Lan C,Weng Z.TLR4 mediates lipotoxic β-cell dysfunction by inhibiting the TMEM24/PI3K/AKT pathway.Acta Biochim Biophys Sin2025;57:1684-95 PMCID:PMC12616714

[64] Gao J,Cai X,Xing J.Therapeutic potential of natural medicines in diabetic kidney disease: restoring lipid homeostasis via lipophagy modulation.Front Pharmacol2025;16:1665339 PMCID:PMC12492015

[65] Han Y,Zhao H.Lipophagy deficiency exacerbates ectopic lipid accumulation and tubular cells injury in diabetic nephropathy.Cell Death Dis2021;12:1031 PMCID:PMC8557213

[66] Li XZ,Xu L.Sarsasapogenin restores podocyte autophagy in diabetic nephropathy by targeting GSK3β signaling pathway.Biochem Pharmacol2021;192:114675

[67] Attie AD,Keller MP.Reversal of hypertriglyceridemia in diabetic BTBR ob/ob mice does not prevent nephropathy.Lab Invest2021;101:935-41 PMCID:PMC9093019

[68] Hatje FA,Sachs W.Tripartite separation of glomerular cell types and proteomes from reporter-free mice.J Am Soc Nephrol2021;32:2175-93 PMCID:PMC8729851

[69] Lei C,Qiu Y.Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1.Cell Death Dis2022;13:184 PMCID:PMC8881581

[70] Zhang C,Yan Y.LncRNA evf-2 exacerbates podocyte injury in diabetic nephropathy by inducing cell cycle re-entry and inflammation through distinct mechanisms triggered by hnRNPU.Adv Sci2024;11:e2406532 PMCID:PMC11653703

[71] Sunilkumar S,Toro AL.Podocyte-specific expression of the stress response protein REDD1 is necessary for diabetes-induced podocytopenia.Diabetes2025;74:398-408 PMCID:PMC11842600

[72] Alonazi AS,Albulayhi LM.Macrophage depletion alleviates immunosenescence in diabetic kidney by modulating GDF-15 and Klotho.Int J Mol Sci2025;26:3990 PMCID:PMC12071727

[73] Barutta F,Mastrocola R.Reversal of albuminuria by combined AM6545 and perindopril therapy in experimental diabetic nephropathy.Br J Pharmacol2018;175:4371-85 PMCID:PMC6240130

[74] Sun H,Yan J.Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease.Nat Commun2022;13:1600 PMCID:PMC8948304

[75] Boi R,Ebefors K,Nyström J.Podocyte geranylgeranyl transferase type-I is essential for maintenance of the glomerular filtration barrier.J Am Soc Nephrol2023;34:641-55 PMCID:PMC10103324

[76] Zhong D,Qiao R.Genetic or pharmacologic blockade of mPGES-2 attenuates renal lipotoxicity and diabetic kidney disease by targeting Rev-Erbα/FABP5 signaling.Cell Rep2024;43:114075

[77] Kong Y,Zhao X.Statins ameliorate cholesterol-induced inflammation and improve AQP2 expression by inhibiting NLRP3 activation in the kidney.Theranostics2020;10:10415-33 PMCID:PMC7482822

[78] Chikatimalla R,Ruhela N.Statins and kidney health: exploring cardiovascular benefits, renal protection, and risks in chronic kidney disease.Postgrad Med2025;137:588-600

[79] Huang CC,Chen WY.Empagliflozin ameliorates free fatty acid induced-lipotoxicity in renal proximal tubular cells via the PPARγ/CD36 pathway in obese mice.Int J Mol Sci2021;22:12408 PMCID:PMC8621539

[80] Ye T,Wu D.Empagliflozin attenuates obesity-related kidney dysfunction and NLRP3 inflammasome activity through the HO-1-adiponectin axis.Front Endocrinol2022;13:907984 PMCID:PMC9248377

[81] Hosokawa K,Sugihara T.Ipragliflozin ameliorates endoplasmic reticulum stress and apoptosis through preventing ectopic lipid deposition in renal tubules.Int J Mol Sci2019;21:190 PMCID:PMC6981520

[82] Sun J,Wang S.Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway.Diabetol Metab Syndr2024;16:38 PMCID:PMC10851504

[83] Di Costanzo A, Esposito G, Indolfi C, Spaccarotella CAM. SGLT2 inhibitors: a new therapeutical strategy to improve clinical outcomes in patients with chronic kidney diseases.Int J Mol Sci2023;24:8732 PMCID:PMC10218404

[84] Hu Q,Xiao X.Flavonoids on diabetic nephropathy: advances and therapeutic opportunities.Chin Med2021;16:74 PMCID:PMC8349014

[85] Sulaiman MK.Molecular mechanisms and therapeutic potential of natural flavonoids in diabetic nephropathy: Modulation of intracellular developmental signaling pathways.Curr Res Pharmacol Drug Discov2024;7:100194 PMCID:PMC11276931

[86] Zheng Y,Han X,Zhao L.Immunomodulatory roles of quercetin in diabetic nephropathy: targeting inflammation, oxidative stress, and ferroptosis.Front Pharmacol2025;16:1687677 PMCID:PMC12657167

[87] Ren G,Yan Y,Qin G.Baicalin exerts a protective effect in diabetic nephropathy by repressing inflammation and oxidative stress through the SphK1/S1P/NF-κB signaling pathway.Diabetes Metab Syndr Obes2023;16:1193-205 PMCID:PMC10149099

[88] Cao Y-L,Hammes H-P.Flavonoids in treatment of chronic kidney disease.Molecules2022;27:2365 PMCID:PMC9000519

[89] Lin CL,Huang YT.A KDM6A-KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction.EMBO Mol Med2019;11:e9828 PMCID:PMC6505577

[90] Liebisch M.Role of epigenetic changes in the pathophysiology of diabetic kidney disease.Glomerular Dis2024;4:211-26 PMCID:PMC11623970

[91] Qu H,Zhu J.Dock5 deficiency promotes proteinuric kidney diseases via modulating podocyte lipid metabolism.Adv Sci2024;11:e2306365 PMCID:PMC10953540

[92] Ding S,Tong JY.Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease.Diabetologia2025;68:1057-75

[93] Chen M,Ge Y,Dworkin L.The redox-sensitive GSK3β is a key regulator of glomerular podocyte injury in type 2 diabetic kidney disease.Redox Biol2024;72:103127 PMCID:PMC10979123

[94] Guo C,Yang A.CHILKBP protects against podocyte injury by preserving ZO-1 expression.Cell Mol Life Sci2022;80:18 PMCID:PMC11072396

[95] Rogg M,Van Wymersch C.α-Parvin defines a specific integrin adhesome to maintain the glomerular filtration barrier.J Am Soc Nephrol2022;33:786-808 PMCID:PMC8970443

[96] Lei X,Ren JG.Astragaloside suppresses apoptosis of the podocytes in rats with diabetic nephropathy via miR-378/TRAF5 signaling pathway.Life Sci2018;206:77-83

[97] Chen X,Tao D.Metadherin orchestrates PKA and PKM2 to activate β-catenin signaling in podocytes during proteinuric chronic kidney disease.Transl Res2024;266:68-83

[98] Njeim R,Kelly CB.A therapeutic lead compound for diabetic kidney disease with a unique lipophagy activation mechanism: SA-OR29.J Am Soc Nephrol2024;35:10.1681/asn.20248p613cev

[99] Njeim R,Donow H.Novel lipophagy inducers as potential therapeutics for lipid metabolism disorders.ACS Chem Biol2025;20:1406-16 PMCID:PMC12614113

[100] Li Q,Shi X.Peroxisome proliferator-activated receptors in kidney diseases: a promising therapeutic target.Biomed Pharmacother2026;195:118983

[101] Suk Kang J,Lee JH.Protective effects of klotho on palmitate-induced podocyte injury in diabetic nephropathy.PLoS One2021;16:e0250666 PMCID:PMC8064606

[102] Rinschen MM,Grahammer F.N-Degradomic analysis reveals a proteolytic network processing the podocyte cytoskeleton.J Am Soc Nephrol2017;28:2867-78 PMCID:PMC5619959