Mitochondrial Dysfunction and Lipid Metabolism Disorder in Podocytes of Diabetic Nephropathy and Exploration of Traditional Chinese Medicine Treatment

Abstract

Abstract: Diabetic nephropathy (DN), one of the microvascular complications of diabetes, is clinically characterized by progressive decrease of albuminuria and glomerular filtration rate. In recent years, the role of podocyte injury in the pathogenesis of DN has become a focus of research. Hemodynamic abnormalities, oxidative stress, autophagy, apoptosis, mitochondrial dysfunction and lipid metabolism disorders all lead to podocyte injury. This paper discusses the relationship between podocyte injury and mitochondrial dysfunction and lipid metabolism disorder in diabetic nephropathy, and summarizes the existing Chinese medicine monomers and compound therapies targeting this pathway and protecting podocyte. The findings summarized here may provide potential therapeutic targets and strategies for the management of DN associated with podocyte injury.

Key words: diabetic nephropathy, podocyte, mitochondrial function, lipid metabolism, Chinese medicine monomers and compound

CLC Number:

R277.5

HUANG Zhen-yu, ZHU Cai-feng, LI Ya-yu, YIN Jia-zhen, YU Cao. Mitochondrial Dysfunction and Lipid Metabolism Disorder in Podocytes of Diabetic Nephropathy and Exploration of Traditional Chinese Medicine Treatment[J]. ZHONGHUA YANGSHENG BAOJIAN, 2025, 43(10): 1-6.

References

[1] ZHANG X X,KONG J,YUN K.Prevalence of Diabetic Nephropathy among Patients with Type 2 Diabetes Mellitus in China:A Meta-Analysis of Observational Studies[J].J Diabetes Res,2020,1:1-11.
[2] RANDO M M,GUTHOFF M,TIWARI V,et al.Editorial:Diagnosis,prevention and treatment in diabetic nephropathy[J].Front Endocrinol (Lausanne),2022,13:1011665.
[3] MARTIN W P,DOCHERTY N G.A Systems Nephrology Approach to Diabetic Kidney Disease Research and Practice[J].Nephron,2024,148(3):127-136.
[4] LI Y,FAN J,ZHU W,et al.Therapeutic Potential Targeting Podocyte Mitochondrial Dysfunction in Focal Segmental Glomerulosclerosis[J]. Kidney Dis (Basel),2023,9(4):254-264.
[5] LI X,ZHANG Y,XING X,et al.Podocyte injury of diabetic nephropathy:Novel mechanism discovery and therapeutic prospects[J].Biomed Pharmacother,2023,168:115670.
[6] AUDZEYENKA I,BIERŻYŃSKA A,LAY A C.Podocyte Bioenergetics in the Development of Diabetic Nephropathy:The Role of Mitochondria[J].Endocrinology,2022,163(1):234.
[7] LIU S,YUAN Y,XUE Y,et al.Podocyte Injury in Diabetic Kidney Disease:A Focus on Mitochondrial Dysfunction[J].Front Cell Dev Biol,2022,10:832887.
[8] OPAZO-RíOS L,MAS S,MARíN-ROYO G,et al.Lipotoxicity and Diabetic Nephropathy:Novel Mechanistic Insights and Therapeutic Opportunities[J].Int J Mol Sci,2020,21(7):2632.
[9] 蓝梦麟,林栩,杨岚茵.足细胞及其标志蛋白在糖尿病肾病诊断价值中的研究进展[J].右江医学,2024,52(1):1-5.
[10] BARUTTA F,BELLINI S,GRUDEN G.Mechanisms of podocyte injury and implications for diabetic nephropathy[J].Clin Sci (Lond),2022,136(7):493-520.
[11] KRAVETS I,MALLIPATTU S K.The Role of Podocytes and Podocyte-Associated Biomarkers in Diagnosis and Treatment of Diabetic Kidney Disease[J].J Endocr Soc,2020,4(4):bvaa029.
[12] FERNáNDEZ-VIZARRA E,UGALDE C.Cooperative assembly of the mitochondrial respiratory chain[J].Trends Biochem Sci,2022,47(12):999-1008.
[13] EFTEKHARPOUR E,FERNYHOUGH P.Oxidative Stress and Mitochondrial Dysfunction Associated with Peripheral Neuropathy in Type 1 Diabetes[J].Antioxid Redox Signal,2022,37(7-9):578-596.
[14] CORTéS-ROJO C,VARGAS-VARGAS M A,OLMOS-ORIZABA B E,et al.Interplay between NADH oxidation by complex I,glutathione redox state and sirtuin-3,and its role in the development of insulin resistance[J].BBA-Mol Basis Dis,2020,1866(8):165801.
[15] SRIVASTAVA A,TOMAR B,SHARMA D,et al.Mitochondrial dysfunction and oxidative stress:Role in chronic kidney disease[J].Life Sci,2023,319:121432.
[16] ZHANG P N,ZHOU M Q,GUO J,et al.Mitochondrial Dysfunction and Diabetic Nephropathy:Nontraditional Therapeutic Opportunities[J].J Diabetes Res,2021,2021:1010268.
[17] ZHAO D M,ZHONG R,WANG X T,et al.Mitochondrial dysfunction in diabetic nephropathy:Insights and therapeutic avenues from traditional Chinese medicine[J].Front Endocrinol (Lausanne),2024,15:1429420.
[18] YANG Y,LIU J,SHI Q,et al.Roles of Mitochondrial Dysfunction in Diabetic Kidney Disease:New Perspectives from Mechanism to Therapy[J].Biomolecules,2024,14(6):733.
[19] YE S,ZHANG M,TANG S C W,et al.PGC1-α in diabetic kidney disease:Unraveling renoprotection and molecular mechanisms[J].Mol Biol Rep,2024,51(1):304.
[20] HAN X,WANG J,LI R,et al.Placental Mesenchymal Stem Cells Alleviate Podocyte Injury in Diabetic Kidney Disease by Modulating Mitophagy via the SIRT1-PGC-1alpha-TFAM Pathway[J].Int J Mol Sci,2023,24(5):4696.
[21] SHEN H,MING Y,XU C,et al.Deregulation of long noncoding RNA (TUG1) contributes to excessive podocytes apoptosis by activating endoplasmic reticulum stress in the development of diabetic nephropathy[J].J Cell Physiol,2019,234(9):15123-15133.
[22] ZHOU D,ZHOU M,WANG Z,et al.PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy[J].Cell Death Dis,2019,10(7):524.
[23] DUGAN L L,YOU Y H,ALI S S,et al.AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function[J].J Clin Invest,2013,123(11):4888-4899.
[24] HONGBO M,YANJIAO D,SHUO W,et al.Podocyte RNF166 deficiency alleviates diabetic nephropathy by mitigating mitochondria impairment and apoptosis via regulation of CYLD signal[J].Biochem Biophys Res Commun,2021,545:46-53.
[25] ZHU J Y,VAN DE LEEMPUT J,HAN Z.Promoting mitochondrial dynamics by inhibiting the PINK1-PRKN pathway to relieve diabetic nephropathy[J].Dis Model Mech,2024,17(4):22-28.
[26] MISE K,LONG J,GALVAN D L,et al.NDUFS4 regulates cristae remodeling in diabetic kidney disease[J].Nat Commun,2024,15(1):1965.
[27] LI T,BAO Y,XIA Y,et al.Loss of MTX2 causes mitochondrial dysfunction,podocyte injury,nephrotic proteinuria and glomerulopathy in mice and patients[J].Int J Biol Sci,2024,20(3):937-952.
[28] LI X,YANG Q,LIU S,et al.Mitochondria-associated endoplasmic reticulum membranes promote mitochondrial fission through AKAP1-Drp1 pathway in podocytes under high glucose conditions[J].Exp Cell Res,2023,424(2):113512.
[29] YUAN D,LI H,DAI W,et al.IGF2BP3-stabilized CAMK1 regulates the mitochondrial dynamics of renal tubule to alleviate diabetic nephropathy[J].BBA-Mol Basis Dis,2024,1870(3):167022.
[30] ISING C,KOEHLER S,BRäHLER S,et al.Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure[J].EMBO Mol Med,2015,7(3):275-287.
[31] YANG L,XU L,HAO X,et al.An aldose reductase inhibitor,WJ-39,ameliorates renal tubular injury in diabetic nephropathy by activating PINK1/Parkin signaling[J].Eur J Pharmacol,2024,967:176376.
[32] 梁凯,刘媛,周策凡,等.Rab蛋白在自噬中的作用[J].生物技术,2023,33(6):785-790,797.
[33] FU Y,SUN Y,WANG M,et al.Elevation of JAML Promotes Diabetic Kidney Disease by Modulating Podocyte Lipid Metabolism[J].Cell Metab,2020,32(6):1052-1062,e8.
[34] 付艺. JAML在糖尿病肾病足细胞脂质代谢稳态失衡中的作用及机制[D].济南:山东大学,2021.
[35] 韩越. iRhom2在糖尿病肾病中的作用研究[D].济南:山东大学,2021.
[36] LU J,CHEN P P,ZHANG J X,et al.GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway[J].Int J Biol Sci,2022,18(1):96-111.
[37] LIU X,DUCASA G M,MALLELA S K,et al.Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome[J].Kidney Int,2020,98(5):1275-1285.
[38] TSUN J G,YUNG S,CHAU M K,et al.Cellular cholesterol transport proteins in diabetic nephropathy[J].PLoS One,2014,9(9):e105787.
[39] HU J,YANG Q,CHEN Z,et al.Small GTPase Arf6 regulates diabetes-induced cholesterol accumulation in podocytes[J].J Cell Physiol,2019,234(12):23559-23570.
[40] YANG Q,HU J,YANG Y,et al.Sirt6 deficiency aggravates angiotensin II-induced cholesterol accumulation and injury in podocytes[J].Theranostics,2020,10(16):7465-7479.
[41] ZUO F W,LIU Z Y,WANG M W,et al.CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice[J].Acta Pharmacol Sin,2024,14(6):733.
[42] HU J,ZHU Z,CHEN Z,et al.Alteration in Rab11-mediated endocytic trafficking of LDL receptor contributes to angiotensin II-induced cholesterol accumulation and injury in podocytes[J].Cell Prolif,2022,55(6):e13229.
[43] QU H,LIU X,ZHU J,et al.Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism[J].Adv Sci (Weinh),2024,11(11):e2306365.
[44] FALKEVALL A,MEHLEM A,PALOMBO I,et al.Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease[J].Cell Metab,2017,25(3):713-726.
[45] LUO Z,CHEN Z,HU J,et al.Interplay of lipid metabolism and inflammation in podocyte injury[J].Metabolism,2024,150:155718.
[46] MATOBA K,TAKEDA Y,NAGAI Y,et al.ROCK2-induced metabolic rewiring in diabetic podocytopathy[J].Commun Biol,2022,5(1):341.
[47] CHEN Q,XIE C,TANG K,et al.The E3 ligase Trim63 promotes podocyte injury and proteinuria by targeting PPARα to inhibit fatty acid oxidation[J].Free Radic Biol Med,2023,209(Pt 1):40-54.
[48] CARRASCO A G,IZQUIERDO-LAHUERTA A,VALVERDE Á M,et al.The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes[J].BBA-Mol Cell Biol Lipids,2023,1868(7):159329.
[49] XIE Y,YUAN Q,TANG B,et al.CPT1A Protects Podocytes from Lipotoxicity and Apoptosis In Vitro and Alleviates Diabetic Nephropathy In Vivo[J].Diabetes,2024,73(6):879-895.
[50] CHEN N,MU L,YANG Z,et al.Carbohydrate response element-binding protein regulates lipid metabolism via mTOR complex1 in diabetic nephropathy[J].J Cell Physiol,2021,236(1):625-640.
[51] HAO Y,FAN Y,FENG J,et al.ALCAT1-mediated abnormal cardiolipin remodelling promotes mitochondrial injury in podocytes in diabetic kidney disease[J].Cell Commun Signal,2024,22(1):26.
[52] MITROFANOVA A,SOSA M A,FORNONI A.Lipid mediators of insulin signaling in diabetic kidney disease[J].Am J Physiol Renal,2019,317(5):F1241-F1252.
[53] WOO C Y,BAEK J Y,KIM A R,et al.Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy[J].Diabetes Metab J,2020,44(4):581-591.
[54] CHEN Z,ZHOU Q,LIU C,et al.Klotho deficiency aggravates diabetes-induced podocyte injury due to DNA damage caused by mitochondrial dysfunction[J].Int J Med Sci,2020,17(17):2763-2772.
[55] ZANG N,CUI C,GUO X,et al.cGAS-STING activation contributes to podocyte injury in diabetic kidney disease[J].iScience,2022,25(10):105145.
[56] FORBES J M,THORBURN D R.Mitochondrial dysfunction in diabetic kidney disease[J].Nat Rev Nephrol,2018,14(5):291-312.
[57] AFSHINNIA F,RAJENDIRAN T M,SONI T,et al.Impaired β-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD[J].J Am Soc Nephrol,2018,29(1):295-306.
[58] HIGGINS G C,COUGHLAN M T.Mitochondrial dysfunction and mitophagy:the beginning and end to diabetic nephropathy?[J].Br J Pharmacol, 2014,171(8):1917-1942.
[59] 郭陈成,张君.中医治疗足细胞损伤的研究进展[J].中国民间疗法,2024,32(3):109-112.
[60] SHEN S,ZHONG H,ZHOU X,et al.Advances in Traditional Chinese Medicine research in diabetic kidney disease treatment[J].Pharm Biol,2024,62(1):222-232.
[61] 柳成,张钧清,王世涛,等.基于足细胞保护探讨黄芪甲苷改善糖尿病肾病的研究进展[J].中医药信息,2024,41(7):1-7.
[62] QIN X,ZHAO Y,GONG J,et al.Berberine Protects Glomerular Podocytes via Inhibiting Drp1-Mediated Mitochondrial Fission and Dysfunction[J].Theranostics,2019,9(6):1698-1713.
[63] QIN X,JIANG M,ZHAO Y,et al.Berberine protects against diabetic kidney disease via promoting PGC-1α-regulated mitochondrial energy homeostasis[J].Br J Pharmacol,2020,177(16):3646-3661.
[64] ZHANG T,CHI Y,KANG Y,et al.Resveratrol ameliorates podocyte damage in diabetic mice via SIRT1/PGC-1α mediated attenuation of mitochondrial oxidative stress[J].J Cell Physiol,2019,234(4):5033-5043.
[65] 朱青青,李雪玲,严佳怡,等.葛根素对高糖环境下H2O2诱导人足细胞氧化应激及线粒体损伤的保护机制[J].北京中医药,2022,41(2):125-131.
[66] ZHONG Y,WANG L,JIN R,et al.Diosgenin Inhibits ROS Generation by Modulating NOX4 and Mitochondrial Respiratory Chain and Suppresses Apoptosis in Diabetic Nephropathy[J].Nutrients,2023,15(9):2164.
[67] ZHANG Y,JIAO X,LIU J,et al.A new direction in Chinese herbal medicine ameliorates for type 2 diabetes mellitus:Focus on the potential of mitochondrial respiratory chain complexes[J].J Ethnopharmacol,2024,321:117484.
[68] JIANG X,YU J,WANG X,et al.Quercetin improves lipid metabolism via SCAP-SREBP2-LDLr signaling pathway in early stage diabetic nephropathy[J].Diabetes Metab Syndr Obes,2019,12:827-839.
[69] SOETIKNO V,SARI F R,SUKUMARAN V,et al.Curcumin decreases renal triglyceride accumulation through AMPK-SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats[J].J Nutr Biochem,2013,24(5):796-802.
[70] ZHANG Q,XIAO X,LI M,et al.Bailing capsule (Cordyceps sinensis) ameliorates renal triglyceride accumulation through the PPARα pathway in diabetic rats[J].Front Pharmacol,2022,13:915592.
[71] CHEN M,CHEN Y,ZHU W,et al.Advances in the pharmacological study of Chinese herbal medicine to alleviate diabetic nephropathy by improving mitochondrial oxidative stress[J].Biomed Pharmacother,2023,165:115088.
[72] GONG M,GUO Y,DONG H,et al.Modified Hu-lu-ba-wan protects diabetic glomerular podocytes via promoting PKM2-mediated mitochondrial dynamic homeostasis[J].Phytomedicine,2024,123:155247.