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Acta Diabetologica

Published in:

11-12-2023 | Diabetic Nephropathy | Original Article

Downregulating lncRNA MIAT attenuates apoptosis of podocytes exposed to high glucose

Authors: Jiayi Xia, Yan Huang, Min Ma, Fang Liu, Bo Cao

Published in: Acta Diabetologica | Issue 4/2024

Abstract

Aims

Diabetic nephropathy (DN), a destructive complication of diabetes mellitus (DM), is one of the leading causes of end-stage renal disease (ESRD). This study aimed to investigate the role of long non-coding RNA (lncRNA) MIAT in high-glucose (HG)-induced podocyte injury associated with DN.

Methods

Three human kidney podocyte (HKP) cultures were treated with HG to mimic DN. Expression of lncRNA MIAT, podocyte-specific and injury-related proteins, and apoptosis were assessed before and after MIAT knockdown using MIAT shRNAs.

Results

MIAT expression was upregulated in HKPs in response to glucose stress. HG treatment resulted in a significant increase in the apoptotic rate, Bax level, and levels of injury-related proteins desmin, fibroblast-specific protein 1 (FSP-1), and smooth muscle α-actin (α-SMA), and a significant reduction in Bcl-2 levels and the levels of podocyte-specific proteins synaptopodin and podocin. Transfection of HKPs with shRNAs significantly reduced MIAT levels (p < 0.05) and attenuated apoptosis in HG-medium. Correspondingly, the levels of synaptopodin and podocin were upregulated, and desmin, FSP-1, and α-SMA were reduced (p < 0.05). Western blot analysis also showed that anti-apoptotic active caspase-3 and Bax and proapoptotic Bcl-2 were elevated and decreased, respectively, after MIAT knockdown, suggesting that apoptosis pathways are deactivated after MIAT downregulation.

Conclusions

High glucose upregulates MIAT level in HKPs and induces cellular injury. Knockdown of MIAT alleviates the injury likely via deactivating apoptosis pathways.

Krug EG (2016) Trends in diabetes: sounding the alarm. Lancet 387(10027):1485–1486. https://doi.org/10.1016/S0140-6736(16)30163-5CrossRefPubMed

Yates T, Khunti K (2016) Epidemiology: the diabetes mellitus tsunami: worse than the ‘spanish flu’ pandemic? Nat Rev Endocrinol 12(7):377–378. https://doi.org/10.1038/nrendo.2016.74CrossRefPubMed

Saeedi P, Petersohn I, Salpea P et al (2019) Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas, 9(th) edn. Diabetes Res Clin Pract 157:107843. https://doi.org/10.1016/j.diabres.2019.107843CrossRefPubMed

Alicic RZ, Rooney MT, Tuttle KR (2017) Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 12(12):2032–2045. https://doi.org/10.2215/CJN.11491116CrossRefPubMedPubMedCentral

Pugliese G, Penno G, Natali A et al (2020) The Italian society of N diabetic kidney disease: new clinical and therapeutic issues. Joint position statement of the Italian diabetes society and the Italian society of nephrology on “The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function.” J Nephrol 33(1):9–35. https://doi.org/10.1007/s40620-019-00650-xCrossRefPubMed

Anders HJ, Davis JM, Thurau K (2016) Nephron protection in diabetic kidney disease. N Engl J Med 375(21):2096–2098. https://doi.org/10.1056/NEJMcibr1608564CrossRefPubMed

Mohandes S, Doke T, Hu H et al (2023) Molecular pathways that drive diabetic kidney disease. J Clin Invest. https://doi.org/10.1172/JCI165654CrossRefPubMedPubMedCentral

Iseki K (2005) Predictors of diabetic end-stage renal disease in Japan. Nephrology (Carlton) 10(Suppl):S2-6. https://doi.org/10.1111/j.1440-1797.2005.00447.xCrossRefPubMed

Murton M, Goff-Leggett D, Bobrowska A et al (2021) Burden of chronic kidney disease by KDIGO categories of glomerular filtration rate and albuminuria: a systematic review. Adv Ther 38(1):180–200. https://doi.org/10.1007/s12325-020-01568-8CrossRefPubMed

10.

Bellier J, Nokin MJ, Larde E et al (2019) Methylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer. Diabetes Res Clin Pract 148:200–211. https://doi.org/10.1016/j.diabres.2019.01.002CrossRefPubMed

11.

Turk Z (2010) Glycotoxines, carbonyl stress and relevance to diabetes and its complications. Physiol Res 59(2):147–156. https://doi.org/10.33549/physiolres.931585CrossRefPubMed

12.

Lotfy M, Adeghate J, Kalasz H, Singh J, Adeghate E (2017) Chronic complications of diabetes mellitus: a mini review. Curr Diabetes Rev 13(1):3–10. https://doi.org/10.2174/1573399812666151016101622CrossRefPubMed

13.

Katakami N (2018) Mechanism of development of atherosclerosis and cardiovascular disease in diabetes mellitus. J Atheroscler Thromb 25(1):27–39. https://doi.org/10.5551/jat.RV17014CrossRefPubMedPubMedCentral

14.

Nagata M (2016) Podocyte injury and its consequences. Kidney Int 89(6):1221–1230. https://doi.org/10.1016/j.kint.2016.01.012CrossRefPubMed

15.

Garg P (2018) A review of podocyte biology. Am J Nephrol 47(Suppl 1):3–13. https://doi.org/10.1159/000481633CrossRefPubMed

16.

Zhang Z, Liang W, Luo Q et al (2021) PFKP activation ameliorates foot process fusion in podocytes in diabetic kidney disease. Front Endocrinol (Lausanne) 12:797025. https://doi.org/10.3389/fendo.2021.797025CrossRefPubMed

17.

Marshall CB (2016) Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic? Am J Physiol Renal Physiol 311(5):F831–F843. https://doi.org/10.1152/ajprenal.00313.2016CrossRefPubMed

18.

Brinkkoetter PT, Ising C, Benzing T (2013) The role of the podocyte in albumin filtration. Nat Rev Nephrol 9(6):328–336. https://doi.org/10.1038/nrneph.2013.78CrossRefPubMed

19.

Menzel S, Moeller MJ (2011) Role of the podocyte in proteinuria. Pediatr Nephrol 26(10):1775–1780. https://doi.org/10.1007/s00467-010-1725-5CrossRefPubMedPubMedCentral

20.

Ishizaka M, Gohda T, Takagi M et al (2015) Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice. Biochem Biophys Res Commun 467(3):549–555. https://doi.org/10.1016/j.bbrc.2015.09.158CrossRefPubMed

21.

Xu B, Meng Y, Jin Y (2021) RNA structures in alternative splicing and back-splicing. Wiley Interdiscip Rev RNA 12(1):e1626. https://doi.org/10.1002/wrna.1626CrossRefPubMed

22.

Nojima T, Proudfoot NJ (2022) Mechanisms of lncRNA biogenesis as revealed by nascent transcriptomics. Nat Rev Mol Cell Biol 23(6):389–406. https://doi.org/10.1038/s41580-021-00447-6CrossRefPubMed

23.

Ghafouri-Fard S, Azimi T, Taheri M (2021) Myocardial infarction associated transcript (MIAT): review of its impact in the tumorigenesis. Biomed Pharmacother 133:111040. https://doi.org/10.1016/j.biopha.2020.111040CrossRefPubMed

24.

Yan B, Yao J, Liu JY et al (2015) lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res 116(7):1143–1156. https://doi.org/10.1161/CIRCRESAHA.116.305510CrossRefPubMed

25.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262CrossRefPubMed

26.

Hirano S (2012) Western blot analysis. Methods Mol Biol 926:87–97. https://doi.org/10.1007/978-1-62703-002-1_6CrossRefPubMed

27.

Patrakka J, Tryggvason K (2010) Molecular make-up of the glomerular filtration barrier. Biochem Biophys Res Commun 396(1):164–169. https://doi.org/10.1016/j.bbrc.2010.04.069CrossRefPubMed

28.

Reiser J, Kriz W, Kretzler M, Mundel P (2000) The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol 11(1):1–8. https://doi.org/10.1681/ASN.V1111CrossRefPubMed

29.

Anil Kumar P, Welsh GI, Saleem MA, Menon RK (2014) Molecular and cellular events mediating glomerular podocyte dysfunction and depletion in diabetes mellitus. Front Endocrinol (Lausanne) 5:151. https://doi.org/10.3389/fendo.2014.00151CrossRefPubMed

30.

Mundel P, Shankland SJ (2002) Podocyte biology and response to injury. J Am Soc Nephrol 13(12):3005–3015. https://doi.org/10.1097/01.asn.0000039661.06947.fdCrossRefPubMed

31.

Kim YH, Goyal M, Kurnit D et al (2001) Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat. Kidney Int 60(3):957–968. https://doi.org/10.1046/j.1523-1755.2001.060003957.xCrossRefPubMed

32.

Tao Y, Chaudhari S, Shotorbani PY et al (2022) Enhanced orai1-mediated store-operated Ca(2+) channel/calpain signaling contributes to high glucose-induced podocyte injury. J Biol Chem 298(6):101990. https://doi.org/10.1016/j.jbc.2022.101990CrossRefPubMedPubMedCentral

33.

Wang M, Hu J, Yan L et al (2019) High glucose-induced ubiquitination of G6PD leads to the injury of podocytes. FASEB J 33(5):6296–6310. https://doi.org/10.1096/fj.201801921RCrossRefPubMed

34.

He X, Zeng X (2020) LncRNA SNHG16 aggravates high glucose-induced podocytes injury in diabetic nephropathy through targeting miR-106a and thereby up-regulating KLF9. Diabetes Metab Syndr Obes 13:3551–3560. https://doi.org/10.2147/DMSO.S271290CrossRefPubMedPubMedCentral

35.

Hu M, Wang R, Li X et al (2017) LncRNA MALAT1 is dysregulated in diabetic nephropathy and involved in high glucose-induced podocyte injury via its interplay with beta-catenin. J Cell Mol Med 21(11):2732–2747. https://doi.org/10.1111/jcmm.13189CrossRefPubMedPubMedCentral

36.

Qi Y, Wu H, Mai C et al (2020) LncRNA-MIAT-mediated miR-214-3p silencing is responsible for IL-17 production and cardiac fibrosis in diabetic cardiomyopathy. Front Cell Dev Biol 8:243. https://doi.org/10.3389/fcell.2020.00243CrossRefPubMedPubMedCentral

37.

Zhang J, Chen M, Chen J et al (2017) Long non-coding RNA MIAT acts as a biomarker in diabetic retinopathy by absorbing miR-29b and regulating cell apoptosis. Biosci Rep. https://doi.org/10.1042/BSR20170036

38.

Meydan C, Uceyler N, Soreq H (2020) Non-coding RNA regulators of diabetic polyneuropathy. Neurosci Lett 731:135058. https://doi.org/10.1016/j.neulet.2020.135058CrossRefPubMed

39.

Zhang M, Zhao S, Xu C et al (2020) Ablation of lncRNA MIAT mitigates high glucose-stimulated inflammation and apoptosis of podocyte via miR-130a-3p/TLR4 signaling axis. Biochem Biophys Res Commun 533(3):429–436. https://doi.org/10.1016/j.bbrc.2020.09.034CrossRefPubMed

40.

Lu XY, Liu BC, Cao YZ et al (2019) High glucose reduces expression of podocin in cultured human podocytes by stimulating TRPC6. Am J Physiol Renal Physiol 317(6):F1605–F1611. https://doi.org/10.1152/ajprenal.00215.2019CrossRefPubMedPubMedCentral

41.

Feng H, Zhu X, Tang Y et al (2021) Astragaloside IV ameliorates diabetic nephropathy in db/db mice by inhibiting NLRP3 inflammasome-mediated inflammation. Int J Mol Med 48(2):1–12. https://doi.org/10.3892/ijmm.2021.4996CrossRef

42.

Zou J, Yaoita E, Watanabe Y et al (2006) Upregulation of nestin, vimentin, and desmin in rat podocytes in response to injury. Virchows Arch 448(4):485–492. https://doi.org/10.1007/s00428-005-0134-9CrossRefPubMed

43.

He M, Li Y, Wang L et al (2020) MYDGF attenuates podocyte injury and proteinuria by activating Akt/BAD signal pathway in mice with diabetic kidney disease. Diabetologia 63(9):1916–1931. https://doi.org/10.1007/s00125-020-05197-2CrossRefPubMed

44.

Ji L, Chen Y, Wang H et al (2019) Overexpression of Sirt6 promotes M2 macrophage transformation, alleviating renal injury in diabetic nephropathy. Int J Oncol 55(1):103–115. https://doi.org/10.3892/ijo.2019.4800CrossRefPubMedPubMedCentral

45.

Asakawa S, Shibata S, Morimoto C et al (2017) Podocyte injury and albuminuria in experimental hyperuricemic model rats. Oxid Med Cell Longev 2017:3759153. https://doi.org/10.1155/2017/3759153CrossRefPubMedPubMedCentral

46.

Reidy K, Susztak K (2009) Epithelial-mesenchymal transition and podocyte loss in diabetic kidney disease. Am J Kidney Dis 54(4):590–593. https://doi.org/10.1053/j.ajkd.2009.07.003CrossRefPubMedPubMedCentral

47.

Ziyadeh FN, Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 4(1):39–45. https://doi.org/10.2174/157339908783502370CrossRefPubMed

48.

Zhang Y, Xi X, Mei Y et al (2019) High-glucose induces retinal pigment epithelium mitochondrial pathways of apoptosis and inhibits mitophagy by regulating ROS/PINK1/Parkin signal pathway. Biomed Pharmacother 111:1315–1325. https://doi.org/10.1016/j.biopha.2019.01.034CrossRefPubMed

Title: Downregulating lncRNA MIAT attenuates apoptosis of podocytes exposed to high glucose
Authors: Jiayi Xia
Yan Huang
Min Ma
Fang Liu
Bo Cao
Publication date: 11-12-2023
Publisher: Springer Milan
Keywords: Diabetic Nephropathy
Diabetes
Published in: Acta Diabetologica / Issue 4/2024
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-023-02213-w

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