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Review Article | Open Access

mTOR pathway: A key player in diabetic nephropathy progression and therapeutic targets

Jingxuan Shia,bXinze LiucYuanyuan JiaodJingwei Tiane,fJiaqi Ana,gGuming ZouaLi Zhuoa()
Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China
China-Japan Friendship Institute of Clinical Medical Sciences, Beijing 100029, China
Beijing University of Chinese Medicine China-Japan Friendship Clinical Medical College, Beijing 100029, China
Department of Nephrology, Fuwai Hospital, Chinese Academy of Medical Science, Beijing 100037, China
Department of Nephrology, Beijing Sixth Hospital, Beijing 100007, China
Capital Medical University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
China-Japan Friendship Clinic Medical College, Peking University, Beijing 100191, China

Peer review under responsibility of Chongqing Medical University.

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Abstract

Diabetic nephropathy is a prevalent complication of diabetes and stands as the primary contributor to end-stage renal disease. The global prevalence of diabetic nephropathy is on the rise, however, due to its intricate pathogenesis, there is currently an absence of efficacious treatments to enhance renal prognosis in affected patients. The mammalian target of rapamycin (mTOR), a serine/threonine protease, assumes a pivotal role in cellular division, survival, apoptosis delay, and angiogenesis. It is implicated in diverse signaling pathways and has been observed to partake in the progression of diabetic nephropathy by inhibiting autophagy, promoting inflammation, and increasing oxidative stress. In this academic review, we have consolidated the understanding of the pathological mechanisms associated with four distinct resident renal cell types (podocytes, glomerular mesangial cells, renal tubular epithelial cells, and glomerular endothelial cells), as well as macrophages and T lymphocytes, within a diabetic environment. Additionally, we highlight the research progress in the treatment of diabetic nephropathy with drugs and various molecules interfering with the mTOR signaling pathway, providing a theoretical reference for the treatment and prevention of diabetic nephropathy.

References

1

Bell S, Fletcher EH, Brady I, et al. End-stage renal disease and survival in people with diabetes: a national database linkage study. QJM. 2015;108(2):127-134.

2

Heerspink HJL, Parving HH, Andress DL, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019;393(10184):1937-1947.

3

Ricciardi CA, Gnudi L. Kidney disease in diabetes: from mechanisms to clinical presentation and treatment strategies. Metabolism. 2021;124:154890.

4

Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-2045.

5

Qi C, Mao X, Zhang Z, Wu H. Classification and differential diagnosis of diabetic nephropathy. J Diabetes Res. 2017;2017:8637138.

6

Yaribeygi H, Mohammadi MT, Rezaee R, Sahebkar A. Crocin improves renal function by declining Nox-4, IL-18, and p53 expression levels in an experimental model of diabetic nephropathy. J Cell Biochem. 2018;119(7):6080-6093.

7

Doshi SM, Friedman AN. Diagnosis and management of type 2 diabetic kidney disease. Clin J Am Soc Nephrol. 2017;12(8):1366-1373.

8

Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903.

9

Liu WJ, Huang WF, Ye L, et al. The activity and role of autophagy in the pathogenesis of diabetic nephropathy. Eur Rev Med Pharmacol Sci. 2018;22(10):3182-3189.

10

Kitada M, Ogura Y, Monno I, Koya D. Regulating autophagy as a therapeutic target for diabetic nephropathy. Curr Diabetes Rep. 2017;17(7):53.

11

Moreno JA, Gomez-Guerrero C, Mas S, et al. Targeting inflammation in diabetic nephropathy: a tale of hope. Expet Opin Invest Drugs. 2018;27(11):917-930.

12

Vallon V, Komers R. Pathophysiology of the diabetic kidney. Compr Physiol. 2011;1(3):1175-1232.

13

Grahammer F, Wanner N, Huber TB. mTOR controls kidney epithelia in health and disease. Nephrol Dial Transplant. 2014;29(Suppl 1):i9-i18.

14

Lieberthal W, Levine JS. Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications. Am J Physiol Ren Physiol. 2012;303(2):F180-F191.

15

Inoki K, Mori H, Wang J, et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011;121(6):2181-2196.

16

Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991;253(5022):905-909.

17

Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994;369(6483):756-758.

18

Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020;21(4):183-203.

19

Kajiwara M, Masuda S. Role of mTOR inhibitors in kidney disease. Int J Mol Sci. 2016;17(6):975.

20

Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471-484.

21

Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122-1128.

22

Gödel M, Hartleben B, Herbach N, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121(6):2197-2209.

23

Puelles VG, van der Wolde JW, Wanner N, et al. mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans. JCI Insight. 2019;4(18):e99271.

24

Qiao S, Liu R, Lv C, et al. Bergenin impedes the generation of extracellular matrix in glomerular mesangial cells and ameliorates diabetic nephropathy in mice by inhibiting oxidative stress via the mTOR/β-TrcP/Nrf2 pathway. Free Radic Biol Med. 2019;145:118-135.

25

Mohan T, Narasimhan KKS, Ravi DB, et al. Role of Nrf2 dysfunction in the pathogenesis of diabetic nephropathy: therapeutic prospect of epigallocatechin-3-gallate. Free Radic Biol Med. 2020;160:227-238.

26

Bao L, Li J, Zha D, et al. Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-κB pathways. Int Immunopharm. 2018;54:245-253.

27

Nagata M. Podocyte injury and its consequences. Kidney Int. 2016;89(6):1221-1230.

28

Hartleben B, Gödel M, Meyer-Schwesinger C, et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest. 2010;120(4):1084-1096.

29

Hong Q, Zhang L, Das B, et al. Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney Int. 2018;93(6):1330-1343.

30

Ding Y, Choi ME. Autophagy in diabetic nephropathy. J Endocrinol. 2015;224(1):R15-R30.

31

Wang W, Sun W, Cheng Y, Xu Z, Cai L. Role of sirtuin-1 in diabetic nephropathy. J Mol Med. 2019;97(3):291-309.

32

Lin TA, Wu VCC, Wang CY. Autophagy in chronic kidney diseases. Cells. 2019;8(1):61.

33

Liu F, Guo J, Qiao Y, et al. miR-138 plays an important role in diabetic nephropathy through SIRT1-p38-TTP regulatory axis. J Cell Physiol. 2021;236(9):6607-6618.

34

Tagawa A, Yasuda M, Kume S, et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes. 2016;65(3):755-767.

35

Zheng D, Tao M, Liang X, Li Y, Jin J, He Q. p66Shc regulates podocyte autophagy in high glucose environment through the Notch-PTEN-PI3K/Akt/mTOR pathway. Histol Histopathol. 2020;35(4):405-415.

36

Zhao X, Chen Y, Tan X, et al. Advanced glycation end-products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB. J Pathol. 2018;245(2):235-248.

37

Zhang Z, Tang S, Gui W, et al. Liver X receptor activation induces podocyte injury via inhibiting autophagic activity. J Physiol Biochem. 2020;76(2):317-328.

38

Luo Q, Liang W, Zhang Z, et al. Compromised glycolysis contributes to foot process fusion of podocytes in diabetic kidney disease: role of ornithine catabolism. Metabolism. 2022;134:155245.

39

Lu Q, Hou Q, Cao K, et al. Complement factor B in high glucose-induced podocyte injury and diabetic kidney disease. JCI Insight. 2021;6(19):e147716.

40

Denhez B, Rousseau M, Spino C, et al. Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1. Sci Rep. 2020;10(1):21628.

41

Das F, Ghosh-Choudhury N, Lee DY, Gorin Y, Kasinath BS, Choudhury GG. Akt2 causes TGFβ-induced deptor downregulation facilitating mTOR to drive podocyte hypertrophy and matrix protein expression. PLoS One. 2018;13(11):e0207285.

42

Ala M. Sestrin2 signaling pathway regulates podocyte biology and protects against diabetic nephropathy. J Diabetes Res. 2023;2023:8776878.

43

Ichimura K, Miyaki T, Kawasaki Y, Kinoshita M, Kakuta S, Sakai T. Morphological processes of foot process effacement in puromycin aminonucleoside nephrosis revealed by FIB/SEM tomography. J Am Soc Nephrol. 2019;30(1):96-108.

44

Fang L, Zhou Y, Cao H, et al. Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury. PLoS One. 2013;8(4):e60546.

45

Lu X, Zhu X, Yu M, Na C, Gan W, Zhang A. Profile analysis reveals transfer RNA fragments involved in mesangial cells proliferation. Biochem Biophys Res Commun. 2019;514(4):1101-1107.

46

Wu Z, Yin W, Sun M, Si Y, Wu X, Chen M. BKCa mediates dysfunction in high glucose induced mesangial cell injury via TGF-β1/Smad2/3 signaling pathways. Internet J Endocrinol. 2020;2020:3260728.

47

Wang X, Gao Y, Tian N, et al. Astragaloside IV represses high glucose-induced mesangial cells activation by enhancing autophagy via SIRT1 deacetylation of NF-κB p65 subunit. Drug Des Dev Ther. 2018;12:2971-2980.

48

Gao C, Fan F, Chen J, et al. FBW7 regulates the autophagy signal in mesangial cells induced by high glucose. BioMed Res Int. 2019;2019:6061594.

49

Wang S, Chen X, Wang M, et al. Long non-coding RNA CYP4B1-PS1-001 inhibits proliferation and fibrosis in diabetic nephropathy by interacting with nucleolin. Cell Physiol Biochem. 2018;49(6):2174-2187.

50

Zhang P, Sun Y, Peng R, et al. Long non-coding RNA Rpph1 promotes inflammation and proliferation of mesangial cells in diabetic nephropathy via an interaction with Gal-3. Cell Death Dis. 2019;10(7):526.

51

Jiang L, Wang R, Fang L, et al. HCP5 is a SMAD3-responsive long non-coding RNA that promotes lung adenocarcinoma metastasis via miR-203/SNAI axis. Theranostics. 2019;9(9):2460-2474.

52

Liang L, Xu J, Wang M, et al. LncRNA HCP5 promotes follicular thyroid carcinoma progression via miRNAs sponge. Cell Death Dis. 2018;9(3):372.

53

Wang X, Liu Y, Rong J, Wang K. LncRNA HCP5 knockdown inhibits high glucose-induced excessive proliferation, fibrosis and inflammation of human glomerular mesangial cells by regulating the miR-93-5p/HMGA2 axis. BMC Endocr Disord. 2021;21(1):134.

54

Yang J, Shen Y, Yang X, et al. Silencing of long noncoding RNA XIST protects against renal interstitial fibrosis in diabetic nephropathy via microRNA-93-5p-mediated inhibition of CDKN1A. Am J Physiol Ren Physiol. 2019;317(5):F1350-F1358.

55

Huang S, Xu Y, Ge X, et al. Long noncoding RNA NEAT1 accelerates the proliferation and fibrosis in diabetic nephropathy through activating Akt/mTOR signaling pathway. J Cell Physiol. 2019;234(7):11200-11207.

56

Kanwar YS, Sun L, Xie P, Liu FY, Chen S. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 2011;6:395-423.

57

Kanwar YS, Jun W, Lin S, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med. 2008;233(1):4-11.

58

Maity S, Bera A, Ghosh-Choudhury N, Das F, Kasinath BS, Choudhury GG. microRNA-181a downregulates deptor for TGFβ-induced glomerular mesangial cell hypertrophy and matrix protein expression. Exp Cell Res. 2018;364(1):5-15.

59

Maity S, Das F, Kasinath BS, Ghosh-Choudhury N, Ghosh Choudhury G. TGFβ acts through PDGFRβ to activate mTORC1 via the Akt/PRAS40 axis and causes glomerular mesangial cell hypertrophy and matrix protein expression. J Biol Chem. 2020;295(42):14262-14278.

60

Lu Q, Zhou Y, Hao M, et al. The mTOR promotes oxidative stress-induced apoptosis of mesangial cells in diabetic nephropathy. Mol Cell Endocrinol. 2018;473:31-43.

61

Xiang H, Xue W, Wu X, et al. FOXP1 inhibits high glucose-induced ECM accumulation and oxidative stress in mesangial cells. Chem Biol Interact. 2019;313:108818.

62

Hartleben B, Wanner N, Huber TB. Autophagy in glomerular health and disease. Semin Nephrol. 2014;34(1):42-52.

63

Klootwijk ED, Reichold M, Unwin RJ, Kleta R, Warth R, Bockenhauer D. Renal Fanconi syndrome: taking a proximal look at the nephron. Nephrol Dial Transplant. 2015;30(9):1456-1460.

64

Lee YH, Kim SH, Kang JM, et al. Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy. Am J Physiol Ren Physiol. 2019;317(4):F767-F780.

65

Haraguchi R, Kohara Y, Matsubayashi K, Kitazawa R, Kitazawa S. New insights into the pathogenesis of diabetic nephropathy: proximal renal tubules are primary target of oxidative stress in diabetic kidney. Acta Histochem Cytoc. 2020;53(2):21-31.

66

Wu M, Zhang M, Zhang Y, et al. Relationship between lysosomal dyshomeostasis and progression of diabetic kidney disease. Cell Death Dis. 2021;12(11):958.

67

Lieberthal W, Levine JS. The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol. 2009;20(12):2493-2502.

68

Kume S. Pathophysiological roles of nutrient-sensing mechanisms in diabetes and its complications. Diabetol Int. 2019;10(4):245-249.

69

Yang T, Hu Y, Chen S, et al. YY1 inactivated transcription co-regulator PGC-1α to promote mitochondrial dysfunction of early diabetic nephropathy-associated tubulointerstitial fibrosis. Cell Biol Toxicol. 2023;39(2):391-413.

70

Lu Q, Wang WW, Zhang MZ, et al. ROS induces epithelial-mesenchymal transition via the TGF-β1/PI3K/Akt/mTOR pathway in diabetic nephropathy. Exp Ther Med. 2019;17(1):835-846.

71

Zhang Y, Zhao S, Wu D, et al. MicroRNA-22 promotes renal tubulointerstitial fibrosis by targeting PTEN and suppressing autophagy in diabetic nephropathy. J Diabetes Res. 2018;2018:4728645.

72

Bera A, Das F, Ghosh-Choudhury N, Mariappan MM, Kasinath BS, Ghosh Choudhury G. Reciprocal regulation of miR-214 and PTEN by high glucose regulates renal glomerular mesangial and proximal tubular epithelial cell hypertrophy and matrix expansion. Am J Physiol Cell Physiol. 2017;313(4):C430-C447.

73

Maity S, Das F, Ghosh-Choudhury N, Kasinath BS, Ghosh Choudhury G. High glucose increases miR-214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis. FEBS Lett. 2019;593(16):2261-2272.

74

Yang S, Fei X, Lu Y, Xu B, Ma Y, Wan H. miRNA-214 suppresses oxidative stress in diabetic nephropathy via the ROS/Akt/mTOR signaling pathway and uncoupling protein 2. Exp Ther Med. 2019;17(5):3530-3538.

75

Shao H, Huang Y, Hu HL, Fan WX, Yin XN. Effect of miR-29c on renal fibrosis in diabetic rats via the AMPK/mTOR signaling pathway. Eur Rev Med Pharmacol Sci. 2019;23(14):6250-6256.

76

Liu L, Pang X, Shang W, Feng G, Wang Z, Wang J. miR-136 improves renal fibrosis in diabetic rats by targeting down-regulation of tyrosine kinase SYK and inhibition of TGF-β1/Smad3 signaling pathway. Ren Fail. 2020;42(1):513-522.

77

Zhuang L, Jin G, Hu X, Yang Q, Shi Z. The inhibition of SGK1 suppresses epithelial-mesenchymal transition and promotes renal tubular epithelial cell autophagy in diabetic nephropathy. Am J Transl Res. 2019;11(8):4946-4956.

78

Ji J, Rong J, Zheng H, et al. Expression profiles of tRNA-derived fragments in high glucose-treated tubular epithelial cells. Exp Ther Med. 2022;25(1):26.

79

Xie Z, Chen Z, Chen J. Combination therapy with Exendin-4 and islet transplantation as a synergistic treatment for diabetic nephropathy in rats. Life Sci. 2021;271:119207.

80

Jeansson M, Haraldsson B. Morphological and functional evidence for an important role of the endothelial cell glycocalyx in the glomerular barrier. Am J Physiol Ren Physiol. 2006;290(1):F111-F116.

81

Matsuda J, Namba T, Takabatake Y, et al. Antioxidant role of autophagy in maintaining the integrity of glomerular capillaries. Autophagy. 2018;14(1):53-65.

82

Gui Z, Suo C, Wang Z, et al. Impaired ATG16L-dependent autophagy promotes renal interstitial fibrosis in chronic renal graft dysfunction through inducing EndMT by NF-κB signal pathway. Front Immunol. 2021;12:650424.

83

Zhang Y, Ma KL, Gong YX, et al. Platelet microparticles mediate glomerular endothelial injury in early diabetic nephropathy. J Am Soc Nephrol. 2018;29(11):2671-2695.

84

Chen X, Chen J, Li X, Yu Z. Activation of mTOR mediates hyperglycemia-induced renal glomerular endothelial hyperpermeability via the RhoA/ROCK/pMLC signaling pathway. Diabetol Metab Syndrome. 2021;13(1):105.

85

Lim JH, Kim HW, Kim MY, et al. Cinacalcet-mediated activation of the CaMKKβ-LKB1-AMPK pathway attenuates diabetic nephropathy in db/db mice by modulation of apoptosis and autophagy. Cell Death Dis. 2018;9(3):270.

86

Hao J, Liu X, Tang J, et al. The effect of allograft inflammatory factor-1 on inflammation, oxidative stress, and autophagy via miR-34a/ATG4B pathway in diabetic kidney disease. Oxid Med Cell Longev. 2022;2022:1668000.

87

Radeva MY, Waschke J. Mind the gap: mechanisms regulating the endothelial barrier. Acta Physiol. 2018;222(1):L419-L422.

88

Zeng LF, Xiao Y, Sun L. A glimpse of the mechanisms related to renal fibrosis in diabetic nephropathy. Adv Exp Med Biol. 2019;1165:49-79.

89

Engel JE, Chade AR. Macrophage polarization in chronic kidney disease: a balancing act between renal recovery and decline? Am J Physiol Ren Physiol. 2019;317(6):F1409-F1413.

90

Calle P, Hotter G. Macrophage phenotype and fibrosis in diabetic nephropathy. Int J Mol Sci. 2020;21(8):2806.

91

Yang Z, Guo Z, Dong J, et al. miR-374a regulates inflammatory response in diabetic nephropathy by targeting MCP-1 expression. Front Pharmacol. 2018;9:900.

92

Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, García-Pérez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7(6):327-340.

93

Tesch GH. Diabetic nephropathy - is this an immune disorder? Clin Sci. 2017;131(16):2183-2199.

94

Ren J, Li J, Feng Y, et al. Rictor/mammalian target of rapamycin complex 2 promotes macrophage activation and kidney fibrosis. J Pathol. 2017;242(4):488-499.

95

Bending JJ, Lobo-Yeo A, Vergani D, Viberti GC. Proteinuria and activated T-lymphocytes in diabetic nephropathy. Diabetes. 1988;37(5):507-511.

96

Bruserud O, Pawelec G. Interleukin-13 secretion by normal and posttransplant T lymphocytes; in vitro studies of cellular immune responses in the presence of acute leukaemia blast cells. Cancer Immunol Immunother. 1997;45(1):45-52.

97

Wu CC, Sytwu HK, Lu KC, Lin YF. Role of T cells in type 2 diabetic nephropathy. Exp Diabetes Res. 2011;2011:514738.

98

Gao Q, Shen W, Qin W, et al. Treatment of db/db diabetic mice with triptolide: a novel therapy for diabetic nephropathy. Nephrol Dial Transplant. 2010;25(11):3539-3547.

99

Chen G, Chen H, Ren S, et al. Aberrant DNA methylation of mTOR pathway genes promotes inflammatory activation of immune cells in diabetic kidney disease. Kidney Int. 2019;96(2):409-420.

100

Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39-68.

101

Young BA, Johnson RJ, Alpers CE, et al. Cellular events in the evolution of experimental diabetic nephropathy. Kidney Int. 1995;47(3):935-944.

102

Kogot-Levin A, Hinden L, Riahi Y, et al. Proximal tubule mTORC1 is a central player in the pathophysiology of diabetic nephropathy and its correction by SGLT2 inhibitors. Cell Rep. 2020;32(4):107954.

103

Reifsnyder PC, Flurkey K, Te A, Harrison DE. Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes. Aging. 2016;8(11):3120-3130.

104

Mori H, Inoki K, Masutani K, et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun. 2009;384(4):471-475.

105

Murakami N, Riella LV, Funakoshi T. Risk of metabolic complications in kidney transplantation after conversion to mTOR inhibitor: a systematic review and meta-analysis. Am J Transplant. 2014;14(10):2317-2327.

106

Paluri RK, Sonpavde G, Morgan C, Rojymon J, Mar AH, Gangaraju R. Renal toxicity with mammalian target of rapamycin inhibitors: a meta-analysis of randomized clinical trials. Oncol Rev. 2019;13(2):455.

107

Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293.

108

Lamming DW, Sabatini DM. A central role for mTOR in lipid homeostasis. Cell Metabol. 2013;18(4):465-469.

109

Shi G, Ozog S, Torbett BE, Compton AA. mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3. Proc Natl Acad Sci U S A. 2018;115(43):E10069-E10078.

110

Flaquer M, Lloberas N, Franquesa M, et al. The combination of sirolimus and rosiglitazone produces a renoprotective effect on diabetic kidney disease in rats. Life Sci. 2010;87(5–6):147-153.

111

Li D, Lu Z, Xu Z, et al. Spironolactone promotes autophagy via inhibiting PI3K/AKT/mTOR signalling pathway and reduce adhesive capacity damage in podocytes under mechanical stress. Biosci Rep. 2016;36(4):e00355.

112

Wang MZ, Wang J, Cao DW, et al. Fucoidan alleviates renal fibrosis in diabetic kidney disease via inhibition of NLRP3 inflammasome-mediated podocyte pyroptosis. Front Pharmacol. 2022;13:790937.

113

Liu H, Wang Q, Shi G, et al. Emodin ameliorates renal damage and podocyte injury in a rat model of diabetic nephropathy via regulating AMPK/mTOR-mediated autophagy signaling pathway. Diabetes Metab Syndr Obes. 2021;14:1253-1266.

114

Lv L, Zhang J, Tian F, Li X, Li D, Yu X. Arbutin protects HK-2 cells against high glucose-induced apoptosis and autophagy by up-regulating microRNA-27a. Artif Cells, Nanomed Biotechnol. 2019;47(1):2940-2947.

115

Lin W, Pan J, Huang E, Zhu Q. Ginkgetin alleviates high glucose-evoked mesangial cell oxidative stress injury, inflammation, and extracellular matrix (ECM) deposition in an AMPK/mTOR-mediated autophagy axis. Chem Biol Drug Des. 2021;98(4):620-630.

116

Dong R, Zhang X, Liu Y, et al. Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via PI3K/AKT/mTOR pathway in diabetic kidney disease. Phytomedicine. 2023;112:154700.

117

Tao M, Zheng D, Liang X, et al. Tripterygium glycoside suppresses epithelial-to-mesenchymal transition of diabetic kidney disease podocytes by targeting autophagy through the mTOR/Twist1 pathway. Mol Med Rep. 2021;24(2):592.

118

Li XY, Wang SS, Han Z, et al. Triptolide restores autophagy to alleviate diabetic renal fibrosis through the miR-141-3p/PTEN/akt/mTOR pathway. Mol Ther Nucleic Acids. 2017;9:48-56.

119

Yang F, Qu Q, Zhao C, et al. Paecilomyces cicadae-fermented Radix astragali activates podocyte autophagy by attenuating PI3K/AKT/mTOR pathways to protect against diabetic nephropathy in mice. Biomed Pharmacother. 2020;129:110479.

120

Guo L, Tan K, Luo Q, Bai X. Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy. Bosn J Basic Med Sci. 2020;20(3):372-380.

121

Wang T, Gao Y, Yue R, et al. Ginsenoside Rg1 alleviates podocyte injury induced by hyperlipidemia via targeting the mTOR/NF-κB/NLRP3 axis. Evid Based Complement Alternat Med. 2020;2020:2735714.

122

Sheng H, Zhang D, Zhang J, et al. Kaempferol attenuated diabetic nephropathy by reducing apoptosis and promoting autophagy through AMPK/mTOR pathways. Front Med. 2022;9:986825.

123

Wang WJ, Jiang X, Gao CC, Chen ZW. Salusin-α mitigates diabetic nephropathy via inhibition of the Akt/mTORC1/p70S6K signaling pathway in diabetic rats. Drug Chem Toxicol. 2022;45(1):283-290.

124

Zhang Y, Wang Y, Luo M, et al. Elabela protects against podocyte injury in mice with streptozocin-induced diabetes by associating with the PI3K/Akt/mTOR pathway. Peptides. 2019;114:29-37.

125

Wu C, Ma X, Zhou Y, Liu Y, Shao Y, Wang Q. Klotho restraining Egr1/TLR4/mTOR axis to reducing the expression of fibrosis and inflammatory cytokines in high glucose cultured rat mesangial cells. Exp Clin Endocrinol Diabetes. 2019;127(9):630-640.

126

Chen DP, Ma YP, Zhuo L, et al. 1, 25-Dihydroxyvitamin D3 inhibits the proliferation of rat mesangial cells induced by high glucose via DDIT4. Oncotarget. 2017;9(1):418-427.

127

Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy. 2021;17(1):1-382.

Genes & Diseases
Article number: 101260
Cite this article:
Shi J, Liu X, Jiao Y, et al. mTOR pathway: A key player in diabetic nephropathy progression and therapeutic targets. Genes & Diseases, 2025, 12(2): 101260. https://doi.org/10.1016/j.gendis.2024.101260
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