臺灣博碩士論文加值系統

糖尿病腎病變（DN）是一種由糖尿病(DM)引起的腎臟疾病。 DN 是全球腎功能衰竭的主要原因，也是糖尿病患者死亡率的最強預測因子。目前的研究認為DM中由血醣及脂質代謝異常所導致的糖脂毒性，在 DN 的發病機制中起重要作用。新綠原酸(nCGA)是一種存在於乾果和其他植物中的植物化學物質。根據以往的研究，nCGA 可以抑制炎症並減少氧化壓力。在本研究中，我們使用了高脂飲食(HFD)餵養db/db小鼠，來模擬糖尿病患者，受到高血糖與高血脂的影響而產生DN的生理環境。並以此模式評估nCGA對糖脂毒性誘導的DN的影響。根據血清生化指標生化和組織病理學結果，nCGA 顯著降低了HFD 餵養的db/db小鼠的腎臟組織變異與纖維化物質堆積，並且nCGA降低了腎臟組織中的氧化壓力，並抑制腎臟組織中的NF-κB發炎路徑活化。另外我們也使用細胞實驗在體外研究了nCGA的分子機制。在小鼠腎絲球系膜細胞MES-13中我們使用高糖(high glucose)模擬糖尿病患者的生理環境，並使用油酸(oleic acid)以建構T2DM患者因糖脂毒性所導致DN發生的模式。根據最終結果，我們驗證了nCGA可以增加抗氧化蛋白Nrf2的表達，並且降低細胞中，由粒線體產生的氧化壓力。本研究還驗證了氧化壓力的上升，是導致NF-κB發炎路徑的過度活化的原因，而nCGA也透過了抑制 NF-κB路徑的過度活化，並在不同的細胞中，降低了炎症因子如TNF-α、MCP-1 的表達。為了更進一步探討nCGA於腎臟中的作用機轉，本研究篩選了四個具有降低氧化壓力或抑制發炎路徑潛力的miRNA，進行分子通路驗證。根據結果顯示，nCGA透過活化靶向為NF-κB之miR-30a，並抑制靶向Nrf2之miR-709，以此抑制發炎反應及氧化壓力，並改善DN。根據以上實驗結果，本研究證實了nCGA通過抑制由糖脂毒性所誘導的氧化壓力，並下調NF-κB信號通路以減少促炎細胞因子產生，減少腎小球變異與腎臟氧化壓力上升，以維持腎功能，最終改善糖尿病腎損傷。目前的結果表明，nCGA 可以通過活化miR-30a 抑制NF-κB路徑抑制發炎反應，並透過抑制miR-709活化Nrf2並降低氧化壓力，改善糖尿病腎病變。未來，我們希望對 nCGA 對 DN 的作用機制進行更多討論，以確定其生物活性。

Diabetic nephropathy (DN) is a kidney disease caused by diabetes mellitus (DM). DN is the leading cause of renal failure worldwide and the strongest predictor of mortality in patients with diabetes. Current research shows that hyperglycemia and hyperlipidemia caused by DM, play an important role in the pathogenesis of DN. Neochlorogenic acid (nCGA) is a phytochemical found in dried fruits and other plants. According to previous studies, nCGA can suppress inflammation and reduce oxidative stress. In this study, we established a T2DM mouse model of DN using high-fat diet (HFD)-fed db/db mice to evaluate the effect of nCGA on DN induced by glucolipotoxicity. Based on the biochemical and histopathological results of serum biochemical markers, nCGA significantly reduced the variation and fibrosis of kidney tissue in HFD-fed db/db mice, and also reduced oxidative stress and inhibited NF-κB pathway to avoid upregulation of inflammatory in kidney tissue factors. The molecular mechanism of nCGA was studied in vitro using mouse mesangial cell line (MES-13). nCGA also suppresses the expression of inflammatory factors, TNF-α and MCP-1 in MES-13 cells by inhibited the overactivation of NF-κB pathway the same results can also be verified in human podocytes. In the other head, nCGA inhibits mitochondria-generated oxidative stress in MES-13 cells by increasing the expression of the antioxidant protein Nrrf2.We further confirmed that the increase of oxidative stress caused by glucolipotoxicity will lead to the overactivation of NF-κB inflammatory pathway. In addition, based on previous experimental results, our study screened four miRNAs with the potential to inhibit inflammation and oxidative stress, in order to further explore the mechanism of nCGA inhibiting diabetic nephropathy. According to the results, nCGA inhibits inflammatory response and oxidative stress and improves DN by activating miR-30a and inhibiting miR-709. In this study, we demonstrated that nCGA inhibits oxidative stress induced by glycolipid toxicity via micro RNAs, and downregulates the NF-κB pathway to reduce pro-inflammatory cytokine production, and to reduce glomerular variability and renal oxidative stress to maintain renal function. The present results suggest that nCGA can inhibit the NF-κB pathway by activating miR-30a, and ameliorate diabetic nephropathy by inhibiting miR-709 to activate Nrf2 and reduce oxidative stress. In the future, we hope to conduct more discussion on the mechanism of action of nCGA on DN to determine its biological activity.

中文摘要 4
英文摘要 6
緒論 9
第一節 糖尿病 9
一、 糖尿病定義與的分類 9
二、 糖尿病的危害 12
第二節 糖尿病腎病變 16
一、 台灣的糖尿病腎病變 16
二、 糖尿病腎病變的成因 17
三、 糖尿病腎病變的機轉 18
四、 氧化壓力 20
五、 NF-κB相關的發炎路徑 21
六、 發炎因子 22
七、 微分子核糖核酸 23
第三節 植化素 26
第四節 研究動機 28
第五節 研究架構 29
實驗器材與藥品 31
實驗方法 37
第一節 動物飼養 37
一、 動物來源 37
二、 動物分組及給藥模式 37
三、 血清生化指標 39
四、 TBARS assay 46
五、 腎臟組織切片 48
六、 西方墨點法（western blotting） 51
第二節 細胞培養 56
一、 MES-13 56
二、 Human podocyte 56
三、 MTT assay 57
四、 DCFDA assay 58
五、 羅丹明(Rhodamine) 59
六、 西方墨點法（western blotting） 60
七、 即時聚合酶連鎖反應(real time-PCR) 62
實驗結果 67
第一節 NCGA對糖尿病腎病變小鼠的生理影響 67
一、 T2DM模式下HFD對體重與血糖的影響 67
二、 nCGA對血清生化指標的影響 69
三、 nCGA對腎臟組織的影響 71
四、 nCGA對腎臟氧化壓力的影響 73
第二節 NCGA對腎臟發炎蛋白表現的影響 74
一、 nCGA對糖尿病腎病變作用機轉 74
二、 誘導模式對於MES-13細胞之影響 75
三、 nCGA對NF-κB相關發炎路徑之影響 76
四、 nCGA於不同腎臟組織細胞中的作用 77
五、 nCGA對T2DM模式細胞中ROS的影響 79
六、 發炎路徑與氧化壓力之間的關係 81
七、 nCGA透過miRNA影響腎病變之機轉 82
結果與討論 84
參考文獻 94
實驗結果圖表 108
附圖 133

1.Lam, D.W., D.J.C.O.i.E. LeRoith, Diabetes, and Obesity, The worldwide diabetes epidemic. 2012. 19(2): p. 93-96.
2.Sun, H., et al., IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. 2022. 183: p. 109119.
3.Daneman, D.J.T.L., Type 1 diabetes. 2006. 367(9513): p. 847-858.
4.Chatterjee, S., K. Khunti, and M.J.J.T.l. Davies, Type 2 diabetes. 2017. 389(10085): p. 2239-2251.
5.Leong, K.S., et al., Obesity and diabetes. 1999. 13(2): p. 221-237.
6.Buchanan, T.A. and A.H.J.T.J.o.c.i. Xiang, Gestational diabetes mellitus. 2005. 115(3): p. 485-491.
7.Wei, W., et al., Oxidative stress, diabetes, and diabetic complications. 2009. 33(5): p. 370-377.
8.Livingstone, S.J., et al., Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008-2010. 2015. 313(1): p. 37-44.
9.R Miranda-Massari, J., et al., Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. 2011. 6(4): p. 260-273.
10.Ramos-Rodriguez, J.J., et al., Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. 2013. 38(11): p. 2462-2475.
11.Matheus, A.S.d.M., et al., Impact of diabetes on cardiovascular disease: an update. 2013. 2013.
12.Selvaraju, V., et al., Diabetes, oxidative stress, molecular mechanism, and cardiovascular disease–an overview. 2012. 22(5): p. 330-335.
13.Lechner, J., O.E. O'Leary, and A.W.J.V.r. Stitt, The pathology associated with diabetic retinopathy. 2017. 139: p. 7-14.
14.Stitt, A.W., et al., The progress in understanding and treatment of diabetic retinopathy. 2016. 51: p. 156-186.
15.Hazlehurst, J.M., et al., Non-alcoholic fatty liver disease and diabetes. 2016. 65(8): p. 1096-1108.
16.Nogueira, P.C.K. and I.d.P.J.J.d.P. Paz, Signs and symptoms of developmental abnormalities of the genitourinary tract. 2016. 92: p. 57-63.
17.MacIsaac, R.J., E.I. Ekinci, and G.J.A.j.o.k.d. Jerums, Markers of and risk factors for the development and progression of diabetic kidney disease. 2014. 63(2): p. S39-S62.
18.Pálsson, R. and U.D.J.A.i.c.k.d. Patel, Cardiovascular complications of diabetic kidney disease. 2014. 21(3): p. 273-280.
19.Viberti, G., J. Yip-Messent, and A.J.D.C. Morocutti, Diabetic nephropathy: future avenue. 1992. 15(9): p. 1216-1225.
20.Harjutsalo, V. and P.-H.J.A.i.c.k.d. Groop, Epidemiology and risk factors for diabetic kidney disease. 2014. 21(3): p. 260-266.
21.Nazar, C.M.J.J.J.o.n., Diabetic nephropathy; principles of diagnosis and treatment of diabetic kidney disease. 2014. 3(1): p. 15.
22.Tryggvason, K.J.J.o.t.A.S.o.N., Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. 1999. 10(11): p. 2440-2445.
23.Kim, Y., et al., Differential expression of basement membrane collagen chains in diabetic nephropathy. 1991. 138(2): p. 413.
24.Persson, F. and P.J.K.i.s. Rossing, Diagnosis of diabetic kidney disease: state of the art and future perspective. 2018. 8(1): p. 2-7.
25.De la Cuesta Benjumea, C.J.I.y.e.e.e., El cuidado del otro: desafíos y posibilidades. 2007. 25(1): p. 106-112.
26.HWANG, S.J., J.C. TSAI, and H.C.J.N. CHEN, Epidemiology, impact and preventive care of chronic kidney disease in Taiwan. 2010. 15: p. 3-9.
27.Lin, S.-F., et al., Quality of life and cognitive assessment in healthy older Asian people with early and moderate chronic kidney disease: The NAHSIT 2013–2016 and validation study. 2022. 17(3): p. e0264915.
28.Hwang, S.-J., 2020 Annual Report on Kidney Disease in Taiwan. 2020, National Health Research Institutes. p. E1-E12, S1-S82 (February 2022).
29.Hsu, C.-C., S.-T. Tu, and W.H.-H.J.J.o.t.F.M.A. Sheu, 2019 Diabetes Atlas: Achievements and challenges in diabetes care in Taiwan. 2019. 118: p. S130-S134.
30.Cove-Smith, A. and B.M.J.N.E.N. Hendry, The regulation of mesangial cell proliferation. 2008. 108(4): p. e74-e79.
31.Fioretto, P. and M. Mauer. Histopathology of diabetic nephropathy. in Seminars in nephrology. 2007. Elsevier.
32.Vleming, L., et al., The glomerular deposition of PAS positive material correlates with renal function in human kidney diseases. 1997. 47(3): p. 158-167.
33.Legouis, D., et al., Renal gluconeogenesis: an underestimated role of the kidney in systemic glucose metabolism. 2020.
34.John, S.J.D., M.S.C. Research, and Reviews, Complication in diabetic nephropathy. 2016. 10(4): p. 247-249.
35.Mogensen, C., C. Christensen, and E.J.D. Vittinghus, The stages in diabetic renal disease: with emphasis on the stage of incipient diabetic nephropathy. 1983. 32(Supplement_2): p. 64-78.
36.Hakim, F.A., A.J.M.s.m.i.m.j.o.e. Pflueger, and c. research, Role of oxidative stress in diabetic kidney disease. 2010. 16(2): p. RA37-48.
37.Jandeleit-Dahm, K., et al., Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy. 1999. 56: p. S31-S36.
38.Prentki, M., et al., Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in β-cell adaptation and failure in the etiology of diabetes. 2002. 51(suppl_3): p. S405-S413.
39.Cerf, M.E.J.M., Cardiac glucolipotoxicity and cardiovascular outcomes. 2018. 54(5): p. 70.
40.Guo, J., et al., Liraglutide reduces hepatic glucolipotoxicity‑induced liver cell apoptosis through NRF2 signaling in Zucker diabetic fatty rats. 2018. 17(6): p. 8316-8324.
41.Yamabe, N., et al., Evaluation of loganin, iridoid glycoside from Corni Fructus, on hepatic and renal glucolipotoxicity and inflammation in type 2 diabetic db/db mice. 2010. 648(1-3): p. 179-187.
42.Abdul-Hadi, M.H., et al., Oxidative stress injury and glucolipotoxicity in type 2 diabetes mellitus: The potential role of metformin and sitagliptin. 2020. 4(2): p. 166.
43.Indo, H.P., et al., A mitochondrial superoxide theory for oxidative stress diseases and aging. 2015. 56(1): p. 1-7.
44.Chatterjee, S., Oxidative stress, inflammation, and disease, in Oxidative stress and biomaterials. 2016, Elsevier. p. 35-58.
45.Coughlan, M.T. and K.J.K.i. Sharma, Challenging the dogma of mitochondrial reactive oxygen species overproduction in diabetic kidney disease. 2016. 90(2): p. 272-279.
46.Schiffer, T.A. and M.J.F.i.p. Friederich-Persson, Mitochondrial reactive oxygen species and kidney hypoxia in the development of diabetic nephropathy. 2017. 8: p. 211.
47.Ferrucci, L. and E.J.N.R.C. Fabbri, Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. 2018. 15(9): p. 505-522.
48.Nennig, S., J.J.A. Schank, and Alcoholism, The role of NFkB in drug addiction: beyond inflammation. 2017. 52(2): p. 172-179.
49.Miyamoto, S., et al., Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B. 1994. 91(26): p. 12740-12744.
50.Greco, R., et al., IkappaB-alpha expression following transient focal cerebral ischemia is modulated by nitric oxide. 2011. 1372: p. 145-151.
51.Yamamoto, Y., et al., IκB kinase α (IKKα) regulation of IKKβ kinase activity. 2000. 20(10): p. 3655-3666.
52.Lawson, C. and S.J.P.r. Wolf, ICAM-1 signaling in endothelial cells. 2009. 61(1): p. 22-32.
53.Hubbard, A.K., R.J.F.r.b. Rothlein, and medicine, Intercellular adhesion molecule-1 (ICAM-1) expression and cell signaling cascades. 2000. 28(9): p. 1379-1386.
54.Yadav, A., V. Saini, and S.J.C.c.a. Arora, MCP-1: chemoattractant with a role beyond immunity: a review. 2010. 411(21-22): p. 1570-1579.
55.Panee, J.J.C., Monocyte Chemoattractant Protein 1 (MCP-1) in obesity and diabetes. 2012. 60(1): p. 1-12.
56.Uchida, K.J.M. and Cells, A lipid-derived endogenous inducer of COX-2: a bridge between inflammation and oxidative stress. 2008. 25(3).
57.Moita, E., et al., Integrated analysis of COX-2 and iNOS derived inflammatory mediators in LPS-stimulated RAW macrophages pre-exposed to Echium plantagineum L. bee pollen extract. 2013. 8(3): p. e59131.
58.Van Rooij, E.J.C.r., The art of microRNA research. 2011. 108(2): p. 219-234.
59.Davis-Dusenbery, B.N. and A.J.T.j.o.b. Hata, Mechanisms of control of microRNA biogenesis. 2010. 148(4): p. 381-392.
60.Nejad, C., H.J. Stunden, and M.P.J.T.F.j. Gantier, A guide to miRNAs in inflammation and innate immune responses. 2018. 285(20): p. 3695-3716.
61.Chang, J.-Y., et al., Development of a miRNA biochip platform. 2014. 6(4): p. 154-158.
62.Cai, Y., et al., A brief review on the mechanisms of miRNA regulation. 2009. 7(4): p. 147-154.
63.Swarbrick, S., et al., Systematic review of miRNA as biomarkers in Alzheimer’s disease. 2019. 56(9): p. 6156-6167.
64.Gjorgjieva, M., et al., miRNAs and NAFLD: from pathophysiology to therapy. 2019. 68(11): p. 2065-2079.
65.Lu, T.X., M.E.J.J.o.a. Rothenberg, and c. immunology, MicroRNA. 2018. 141(4): p. 1202-1207.
66.Conserva, F., et al., Urinary miRNA-27b-3p and miRNA-1228-3p correlate with the progression of kidney fibrosis in diabetic nephropathy. 2019. 9(1): p. 1-11.
67.Sonoda, H., et al., miRNA profiling of urinary exosomes to assess the progression of acute kidney injury. 2019. 9(1): p. 1-11.
68.Patel, V., et al., miR-17∼ 92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease. 2013. 110(26): p. 10765-10770.
69.Dewanjee, S. and N.J.B.p. Bhattacharjee, MicroRNA: a new generation therapeutic target in diabetic nephropathy. 2018. 155: p. 32-47.
70.Wetzel, W.C. and S.R.J.E.L. Whitehead, The many dimensions of phytochemical diversity: linking theory to practice. 2020. 23(1): p. 16-32.
71.Lagoa, R., et al., Advances in phytochemical delivery systems for improved anticancer activity. 2020. 38: p. 107382.
72.Tang, G.-Y., et al., Phytochemical composition and antioxidant capacity of 30 Chinese teas. 2019. 8(6): p. 180.
73.Yadav, R. and M.J.J.o.p. Agarwala, Phytochemical analysis of some medicinal plants. 2011. 3(12).
74.Rodríguez-Gómez, R., et al., Determination of three main chlorogenic acids in water extracts of coffee leaves by liquid chromatography coupled to an electrochemical detector. 2018. 7(10): p. 143.
75.Robbins, R.J.J.J.o.a. and f. chemistry, Phenolic acids in foods: an overview of analytical methodology. 2003. 51(10): p. 2866-2887.
76.Li, Z., et al., Omentin-1 prevents cartilage matrix destruction by regulating matrix metalloproteinases. Biomedicine & Pharmacotherapy, 2017. 92: p. 265-269.
77.Sato, Y., et al., In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. International Journal of Pharmaceutics, 2011. 403(1): p. 136-138.
78.Marques, V. and A. Farah, Chlorogenic acids and related compounds in medicinal plants and infusions. Food Chemistry, 2009. 113(4): p. 1370-1376.
79.Cho, A.-S., et al., Chlorogenic acid exhibits anti-obesity property and improves lipid metabolism in high-fat diet-induced-obese mice. Food and Chemical Toxicology, 2010. 48(3): p. 937-943.
80.Park, S.Y., et al., Neochlorogenic acid inhibits against LPS-activated inflammatory responses through up-regulation of Nrf2/HO-1 and involving AMPK pathway. 2018. 62: p. 1-10.
81.Gao, X.-h., et al., Anti-inflammatory effects of neochlorogenic acid extract from mulberry leaf (Morus alba L.) against LPS-stimulated inflammatory response through mediating the AMPK/Nrf2 signaling pathway in A549 cells. 2020. 25(6): p. 1385.
82.Sharma, K., P. McCue, and S.R.J.A.J.o.P.-R.P. Dunn, Diabetic kidney disease in the db/db mouse. 2003. 284(6): p. F1138-F1144.
83.Poitout, V. and R.P.J.E.r. Robertson, Glucolipotoxicity: fuel excess and β-cell dysfunction. 2008. 29(3): p. 351-366.
84.Liu, Y., et al., Resistance exercise intensity is correlated with attenuation of HbA1c and insulin in patients with type 2 diabetes: a systematic review and meta-analysis. 2019. 16(1): p. 140.
85.Quispe, R., et al., Triglycerides to high-density lipoprotein–cholesterol ratio, glycemic control and cardiovascular risk in obese patients with type 2 diabetes. 2016. 23(2): p. 150-156.
86.Sohrabi, Y., D. Schwarz, and H.J.T.i.M.M. Reinecke, LDL-C augments whereas HDL-C prevents inflammatory innate immune memory. 2022. 28(1): p. 1-4.
87.Li, J., et al., Podocyte biology in diabetic nephropathy. 2007. 72: p. S36-S42.
88.Tung, C.W., et al., Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. 2018. 23: p. 32-37.
89.Haneda, M., et al., Overview of glucose signaling in mesangial cells in diabetic nephropathy. 2003. 14(5): p. 1374-1382.
90.Alsaad, K. and A.J.J.o.c.p. Herzenberg, Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update. 2007. 60(1): p. 18-26.
91.Yiu, W.H., et al., Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress. 2016. 89(2): p. 386-398.
92.Elmarakby, A.A. and J.C.J.C.t. Sullivan, Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. 2012. 30(1): p. 49-59.
93.Cvetković, T., et al., Oxidative stress parameters as possible urine markers in patients with diabetic nephropathy. 2009. 23(5): p. 337-342.
94.Mezzano, S., et al., NF-κB activation and overexpression of regulated genes in human diabetic nephropathy. 2004. 19(10): p. 2505-2512.
95.López‐Ongil, S., et al., Role of reactive oxygen species in the signalling cascade of cyclosporine A‐mediated up‐regulation of eNOS in vascular endothelial cells. 1998. 124(3): p. 447-454.
96.Henderson, J.R., et al., The development and in vitro characterisation of an intracellular nanosensor responsive to reactive oxygen species. 2009. 24(12): p. 3608-3614.
97.Brawek, B., et al., Reactive oxygen species (ROS) in the human neocortex: Role of aging and cognition. 2010. 81(4-5): p. 484-490.
98.Li, S., et al., Inhibiting Rab27a in renal tubular epithelial cells attenuates the inflammation of diabetic kidney disease through the miR-26a-5p/CHAC1/NF-kB pathway. 2020. 261: p. 118347.
99.Simpson, K., et al., MicroRNAs in diabetic nephropathy: from biomarkers to therapy. 2016. 16(3): p. 1-7.
100.Gross, J.L., et al., Diabetic nephropathy: diagnosis, prevention, and treatment. 2005. 28(1): p. 164-176.
101.Punithavathi, V.R., et al., Antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic Wistar rats. 2011. 650(1): p. 465-471.
102.Muthukumaran, J., et al., Syringic acid, a novel natural phenolic acid, normalizes hyperglycemia with special reference to glycoprotein components in experimental diabetic rats. 2013. 2(4): p. 304-309.
103.Khan, S., et al., Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression. 2020. 5(15).
104.Bobulescu, I.A.J.C.o.i.n. and hypertension, Renal lipid metabolism and lipotoxicity. 2010. 19(4): p. 393.
105.Yamamoto, T., et al., High-fat diet–induced lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in the kidney. 2017. 28(5): p. 1534-1551.
106.Schena, F.P. and L.J.J.o.t.A.s.o.n. Gesualdo, Pathogenetic mechanisms of diabetic nephropathy. 2005. 16(3 suppl 1): p. S30-S33.
107.Jia, Y., et al., Dapagliflozin aggravates renal injury via promoting gluconeogenesis in db/db mice. 2018. 45(5): p. 1747-1758.
108.Huang, L., et al., Development of a chronic kidney disease model in C57BL/6 mice with relevance to human pathology. 2013. 3(1): p. 12-29.
109.Chen, H.-W., et al., Nelumbo nucifera leaves extract attenuate the pathological progression of diabetic nephropathy in high-fat diet-fed and streptozotocin-induced diabetic rats. 2019. 27(3): p. 736-748.
110.Li, L., et al., Chlorogenic acids in cardiovascular disease: A review of dietary consumption, pharmacology, and pharmacokinetics. 2020. 68(24): p. 6464-6484.
111.Navarro-González, J.F., et al., Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. 2011. 7(6): p. 327-340.
112.Abboud, H.E.J.E.c.r., Mesangial cell biology. 2012. 318(9): p. 979-985.
113.Dalla Vestra, M., et al., Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. 2003. 52(4): p. 1031-1035.
114.Dasari, D., et al., Canagliflozin and Dapagliflozin Attenuate Glucolipotoxicity-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Inhibition of Sodium-Glucose Cotransporter-1. 2022. 5(4): p. 216-225.
115.Turkmen, K.J.I.u. and nephrology, Inflammation, oxidative stress, apoptosis, and autophagy in diabetes mellitus and diabetic kidney disease: the Four Horsemen of the Apocalypse. 2017. 49(5): p. 837-844.
116.Wada, J. and H.J.C.s. Makino, Inflammation and the pathogenesis of diabetic nephropathy. 2013. 124(3): p. 139-152.
117.Jiang, X., et al., MiR-30a targets IL-1α and regulates islet functions as an inflammation buffer and response factor. 2017. 7(1): p. 1-15.
118.Xie, L., et al., Significance of a tumor microenvironment-mediated P65-miR-30a-5p-BCL2L11 amplification loop in multiple myeloma. 2022. 415(1): p. 113113.
119.Yani, Z., C.J.C.J.o.N. Meichu, Dialysis, and Transplantation, MicroRNA in protecting mitochondrial function and delaying acute renal injury. 2020. 29(6): p. 557.
120.Surendran, S., et al., Gene targets of mouse miR-709: regulation of distinct pools. 2016. 6(1): p. 1-10.
121.Guo, Y., et al., MicroRNA-709 mediates acute tubular injury through effects on mitochondrial function. 2018. 29(2): p. 449-461.
122.Brandenburger, T., et al., Noncoding RNAs in acute kidney injury. 2018. 94(5): p. 870-881.