2型糖尿病小鼠模型构建的研究进展
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摘要
2型糖尿病(type 2 diabetes mellitus, T2DM)的病因主要在于细胞控制动态平衡能力的缺失,以及这些细胞所构成的组织或器官功能的失调。为了更好地研究和治疗2型糖尿病,人们借助不同动物模型去了解不同细胞、组织和器官的功能。在动物模型的选择上,小鼠因为其基因和表型能很好地模拟2型糖尿病而被广泛使用。2型糖尿病小鼠模型种类繁多,包括:自发突变性模型、热量过量性模型、外科和化学诱导性模型、常用转基因小鼠模型、专门用于研究环境对基因影响性的模型、CRISPR-Cas9构建模型以及特定的糖尿病肾病模型。本文就2型糖尿病现有的小鼠动物模型及其构建的方式给予简要综述,以期帮助广大科研工作者了解并更好地选择2型糖尿病小鼠实验模型。
Type 2 diabetes mellitus(T2 DM) is driven by defects of cellular function in regulating energy homeostasis, and the dysfunction of tissues or organs composed of these cells. In order to investigate and treat T2 DM, researchers have to use animal models to reveal the contributions of different cells, tissues and organs. Mice are widely used for T2 DM research, since comparative studies and human disease modelling could be performed with well-characterised mouse strains(in terms of their genotype and phenotype). There are many ways to obtain mouse models in study of T2 DM, such as spontaneous mutations that lead to obesity and diabetes, caloric excess, surgical and chemical induction, genetic mutation created by transgenic and gene knockout technologies. There are also other mouse models, including those for understanding interactions between genes and environment, peripheral models generated by CRISPR/Cas9 approaches, and models of diabetic nephropathy. Herein, the methods and techniques of constructing T2 DM animal models were discussed to help researchers in understanding and choosing T2 DM mouse models.
Type 2 diabetes mellitus(T2 DM) is driven by defects of cellular function in regulating energy homeostasis, and the dysfunction of tissues or organs composed of these cells. In order to investigate and treat T2 DM, researchers have to use animal models to reveal the contributions of different cells, tissues and organs. Mice are widely used for T2 DM research, since comparative studies and human disease modelling could be performed with well-characterised mouse strains(in terms of their genotype and phenotype). There are many ways to obtain mouse models in study of T2 DM, such as spontaneous mutations that lead to obesity and diabetes, caloric excess, surgical and chemical induction, genetic mutation created by transgenic and gene knockout technologies. There are also other mouse models, including those for understanding interactions between genes and environment, peripheral models generated by CRISPR/Cas9 approaches, and models of diabetic nephropathy. Herein, the methods and techniques of constructing T2 DM animal models were discussed to help researchers in understanding and choosing T2 DM mouse models.
引文
[1] DA SILVA XAVIER G, HODSON D J. Mouse models of peripheral metabolic disease[J]. Best Practice&Research. Clinical Endocrinology&Metabolism, 2018, 32(3):299-315.
[2] BARRIOS-CORREA A A, ESTRADA J A, CONTRERAS I. Leptin signaling in the control of metabolism and appetite:lessons from animal models[J]. Journal of Molecular Neuroscience, 2018,10(3):1-13.
[3] KHOR V K, TONG M H, QIAN Y, et al. Gender-specific expression and mechanism of regulation of estrogen sulfotransferase in adipose tissues of the mouse[J]. Endocrinology, 2008,149(11):5440-5448.
[4] BRODERICK T L, JANKOWSKI M, GUTKOWSKA J. The effects of exercise training and caloric restriction on the cardiac oxytocin natriuretic peptide system in the diabetic mouse[J].Diabetes, Metabolic Syndrome and Obesity:Targets and Therapy, 2017, 11(10):1027-1036.
[5] CHAE Y J, SONG J S, AHN J H, et al. Model-based pharmacokinetic and pharmacodynamic analysis for acute effects of a small molecule inhibitor of diacylglycerol acyltransferase-1 in the TallyHo/JngJ polygenic mouse[J]. Xenobiotica, 2018, 49(7):823-832.
[6] WANG Q, ZHANG P, APRECIO R, et al. Comparison of experimental diabetic periodontitis induced by Porphyromonas gingivalis in mice[J]. Journal of Diabetes Research, 2016, 2016:4840203.
[7] TOMINO Y. Lessons from the KK-Ay mouse, a spontaneous animal model for the treatment of human type 2 diabetic nephropathy[J]. Nephro-Urology Monthly, 2012, 4(3):524-529.
[8] NISHIMURA M. Breeding of mouse strains for diabetes mellitus[J]. Experimental Animals, 1969, 18:147-157.
[9] HORI M, MUTOH M, ISHIGAMORI R, et al. Activated ductal proliferation induced by N-nitrosobis(2-oxopropyl)amine in fatinfiltrated pancreas of KK-Ay mice[J]. In Vivo(Athens, Greece),2018, 32(3):499-505.
[10] ZHANG Y, MO F F, ZHANG D W, et al. Jiangtang Xiaoke granule attenuates glucose metabolism disorder via regulating endoplasmic reticulum stress in the liver of type 2 diabetes mellitus mice[J]. Journal of Traditional Chinese Medicine, 2018,38(4):110-118.
[11] YOSHINARI O, IGARASHI K. Anti-diabetic effect of pyroglutamic acid in type 2 diabetic Goto-Kakizaki rats and KKAy mice[J]. British Journal of Nutrition, 2011, 106(7):995-1004.
[12] QIN Z X, WANG W, LIAO D Q, et al. UPLC-Q/TOF-MS-based serum metabolomics reveals hypoglycemic effects of Rehmannia glutinosa, Coptis chinensis and their combination on high-fatdiet-induced diabetes in KK-Ay mice[J]. International Journal of Molecular Sciences, 2018, 19(12):3984.
[13] INAGAWA H, SAIKA T, NISHIYAMA N, et al. Dewaxed brown rice feed improves fatty liver in obese and diabetic model mice[J].Anticancer Research, 2018, 38(7):4339-4345.
[14] WANG B, CHANDRASEKERA P C, PIPPIN J J. Leptin-and leptin receptor-deficient rodent models:relevance for human type 2 diabetes[J]. Current Diabetes Reviews, 2014, 10(2):131-145.
[15] ZHANG Y, PROENEA R, MAFFEI M, et al. Positional cloning of the mouse obese gene and its human homologue[J]. Nature,1994, 372(6505):425-432.
[16] WANG C Y, LIAO J K. A mouse model of diet-induced obesity and insulin resistance[J]. Methods in Molecular Biology, 2012,821:421-433.
[17] MONTGOMERY M K, HALLAHAN N L, BROWN S H, et al.Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding[J]. Diabetologia, 2013, 56(5):1129-1139.
[18] PEYOT M L, PEPIN E, LAMINTAGNE J, et al. Beta-cell failure in diet-induced obese mice stratified according to body weight gain:secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta-cell mass[J]. Diabetes, 2010,59(9):2178-2187.
[19] PETTERSSON U S, WALDEN T B, CARLSSON P O, et al. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue[J]. PLoS One, 2012, 7(9):e46057.
[20] VILLARROYA F, CEREIJO R, GAVALDA-NAVARRO A, et al.Inflammation of brown/beige adipose tissues in obesity and metabolic disease[J]. Journal of Internal Medicine, 2018, 284(5):492-504.
[21] LOWELL B B, S-SUSULIE V, HAMANN A, et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue[J]. Nature, 1993, 366(6457):740-742.
[22] DE LAS HERAS N, KLETT-MINGO M, BALLESTEROS S, et al.Chronic exercise improves mitochondrial function and insulin sensitivity in brown adipose tissue[J]. Frontiers in Physiology,2018, 9:1122.
[23] HALBAN P A, POLONSKY K S, BOWDEN D W, et al.β-cell failure in type 2 diabetes:postulated mechanisms and prospects for prevention and treatment[J]. Diabetes Care, 2014, 37(6):1751-1758.
[24] LENZEN S. The mechanisms of alloxan-and streptozotocininduced diabetes[J]. Diabetologia, 2008, 51(2):216-226.
[25] ASRAFUZZAMAN M, CAO Y, AFROZ R, et al. Animal models for assessing the impact of natural products on the aetiology and metabolic pathophysiology of type 2 diabetes[J]. Biomedicine&Pharmacotherapy, 2017, 89:1242-1251.
[26] VANKRIEKEN P P, DICKER A, ERIKSSON M, et al. Kinetics of functional beta cell mass decay in a diphtheria toxin receptor mouse model of diabetes[J]. Scientific Reports, 2017, 7:12440.
[27] JIMENEZ V, AYUSO E, MALLOL C, et al. In vivo genetic engineering of murine pancreatic beta cells mediated by singlestranded adeno-associated viral vectors of serotypes 6, 8 and 9[J].Diabetologia, 2011, 54(5):1075-1086.
[28] SAMUEL V T, SHULMAN G I. Mechanisms for insulin resistance:common threads and missing links[J]. Cell, 2012, 148(5):852-871.
[29] UNGER R H, CHERRINGTON A D. Glucagonocentric restruc turing of diabetes:a pathophysiologic and therapeutic makeover[J]. The Journal of Clinical Investigation, 2012, 122(1):4-12.
[30] FOLLO F, LA ROSA S, FINZI G, et al. Pancreatic islet of Langerhans’cytoarchitecture and ultrastructure in normal glu cose tolerance and in type 2 diabetes mellitus[J]. Diabetes, Obesity&Metabolism, 2018, 20(2):137-144.
[31] HONDA A, KOMIYA K, HARA A, et al. Normal pancreaticβ-cell function in mice with RIP-Cre-mediated inactivation of p62/SQSTM1[J]. Endocrine Journal, 2018, 65(1):83-89.
[32] WICKSTEED B, BRISSOVA M, YAN W, et al. Conditional gene targeting in mouse pancreaticβ-cells:analysis of ectopic Cre transgene expression in the brain[J]. Diabetes, 2010, 59(12):3090-3098.
[33] BROUWERS B, DE FAUDEUR G, OSIPOVICH A B, et al.Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression[J]. Cell Metabolism, 2014, 20(6):979-990.
[34] THORENS B, TARUSSIO D, MAESTRO M A, et al. Ins1Cre knock-in mice for beta cell-specific gene recombination[J]. Diabetologia, 2015, 58(3):558-565.
[35] ACKERMANN A M, ZHANG J, HELLER A, et al. High-fidelity Glucagon-CreER mouse line generated by CRISPRCas9 assisted gene targeting[J]. Molecular Metabolism, 2017, 6(3):236-244.
[36] SHI X, CHACKO S, LI F, et al. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity[J]. Molecular Metabolism, 2017, 6(11):1350-1359.
[37] SOEDLING H, HODSON D J, ADRIANSSENS A E, et al.Limited impact on glucose homeostasis of leptin receptor deletion from insulin-or proglucagon-expressing cells[J]. Molecular Metabolism, 2015, 4(9):619-630.
[38] ABEL E D, PERONI O, KIM J K, et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver[J]. Nature, 2001, 409(6821):729-733.
[39] GUILLAM M T, HUMMLER E, SCHAERER E, et al. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2[J]. Nature Genetics, 1997, 17(3):327-330.
[40] SONE H, SUZUKI H, TAKAHASHI A, et al. Disease model:hyperinsulinemia and insulin resistance:part A—targeted disruption of insulin signaling or glucose transpor[J]. Trends in Molecular Medicine, 2001, 7(8):320-322.
[41] DIEESLER S, JAN M, EMMENEGGER Y, et al. A systems genetics resource and analysis of sleep regulation in the mouse[J].PLoS Biology, 2018, 16(8):e2005750.
[42] ANDREUX P A, WILLIAMS E G, KOUTNIKOVA H, et al.Systems genetics of metabolism:the use of the BXD murine reference panel for multiscalar integration of traits[J]. Cell, 2012,150(6):1287-1299.
[43] CLAUSSNITZER M, DANKEL S N, KIM K H, et al. FTO obesity variant circuitry and adipocyte browning in humans[J]. The New England Journal of Medicine, 2015, 373(10):895-907.
[44] DA SILVA XAVIER G, BELLOMO E A, MCGINTY J A, et al.Animal models of GWAS-identified type 2 diabetes genes[J].Journal of Diabetes Research, 2013, 2013:906590.
[45] AZUSHIMA K, GURLEY S B, COFFMAN T M. Modelling diabetic nephropathy in mice[J]. Nature Reviews Nephrology, 2018,14(1):48-56.
[46] ZHAO H J, WANG S, CHENG H, et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice[J]. Journal of the American Society of Nephrology, 2006, 17(10):2664-2669.
[47] MOHAN S, REDDICK R L, MUSI N, et al. Diabetic eNOS knockout mice develop distinct macro-and microvascular complications[J]. Laboratory Investigation, 2015, 88(5):515-528.
[48] ZHANG M Z, WANG S, YANG S, et al. Role of blood pressure and the renin-angiotensin system in development of dia betic nephropathy(DN)in eNOS-/-db/db mice[J]. American Journal of Physiology:Renal Physiology, 2012, 302(4):F433-F438.
[49] HUDKINS K L, PICHAIWONG W, WIETECHA T, et al. BTBR ob/ob mutant mice model progressive diabetic nephropathy[J].Journal of the American Society of Nephrology, 2010, 21(9):1533-1542.
[50] KORZH V, GRUNWALD D. Nadine Dobrovolska觙a-Zavadska觙a and the dawn of developmental genetics[J]. Bioessays, 2001, 23(4):365-371.
[51] CLEE S M, NADLEER S T, ATTIE A D. Genetic and genomic studies of the BTBR ob/ob mouse model of type 2 diabetes[J].American Journal of Therapeutics, 2005, 12(6):491-498.
[52] MERSCHER-GOMEZ S, GUZMAN J, PEDIGO C E, et al.Cyclodextrin protects podocytes in diabetic kidney disease[J].Diabetes, 2013, 62(11):3817-3827.
[53] GEMBARDT F, BARTAUN C, JARZEBSKA N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension[J]. American Journal of Physiology:Renal Physiology, 2014, 307(3):F317-F325.
[2] BARRIOS-CORREA A A, ESTRADA J A, CONTRERAS I. Leptin signaling in the control of metabolism and appetite:lessons from animal models[J]. Journal of Molecular Neuroscience, 2018,10(3):1-13.
[3] KHOR V K, TONG M H, QIAN Y, et al. Gender-specific expression and mechanism of regulation of estrogen sulfotransferase in adipose tissues of the mouse[J]. Endocrinology, 2008,149(11):5440-5448.
[4] BRODERICK T L, JANKOWSKI M, GUTKOWSKA J. The effects of exercise training and caloric restriction on the cardiac oxytocin natriuretic peptide system in the diabetic mouse[J].Diabetes, Metabolic Syndrome and Obesity:Targets and Therapy, 2017, 11(10):1027-1036.
[5] CHAE Y J, SONG J S, AHN J H, et al. Model-based pharmacokinetic and pharmacodynamic analysis for acute effects of a small molecule inhibitor of diacylglycerol acyltransferase-1 in the TallyHo/JngJ polygenic mouse[J]. Xenobiotica, 2018, 49(7):823-832.
[6] WANG Q, ZHANG P, APRECIO R, et al. Comparison of experimental diabetic periodontitis induced by Porphyromonas gingivalis in mice[J]. Journal of Diabetes Research, 2016, 2016:4840203.
[7] TOMINO Y. Lessons from the KK-Ay mouse, a spontaneous animal model for the treatment of human type 2 diabetic nephropathy[J]. Nephro-Urology Monthly, 2012, 4(3):524-529.
[8] NISHIMURA M. Breeding of mouse strains for diabetes mellitus[J]. Experimental Animals, 1969, 18:147-157.
[9] HORI M, MUTOH M, ISHIGAMORI R, et al. Activated ductal proliferation induced by N-nitrosobis(2-oxopropyl)amine in fatinfiltrated pancreas of KK-Ay mice[J]. In Vivo(Athens, Greece),2018, 32(3):499-505.
[10] ZHANG Y, MO F F, ZHANG D W, et al. Jiangtang Xiaoke granule attenuates glucose metabolism disorder via regulating endoplasmic reticulum stress in the liver of type 2 diabetes mellitus mice[J]. Journal of Traditional Chinese Medicine, 2018,38(4):110-118.
[11] YOSHINARI O, IGARASHI K. Anti-diabetic effect of pyroglutamic acid in type 2 diabetic Goto-Kakizaki rats and KKAy mice[J]. British Journal of Nutrition, 2011, 106(7):995-1004.
[12] QIN Z X, WANG W, LIAO D Q, et al. UPLC-Q/TOF-MS-based serum metabolomics reveals hypoglycemic effects of Rehmannia glutinosa, Coptis chinensis and their combination on high-fatdiet-induced diabetes in KK-Ay mice[J]. International Journal of Molecular Sciences, 2018, 19(12):3984.
[13] INAGAWA H, SAIKA T, NISHIYAMA N, et al. Dewaxed brown rice feed improves fatty liver in obese and diabetic model mice[J].Anticancer Research, 2018, 38(7):4339-4345.
[14] WANG B, CHANDRASEKERA P C, PIPPIN J J. Leptin-and leptin receptor-deficient rodent models:relevance for human type 2 diabetes[J]. Current Diabetes Reviews, 2014, 10(2):131-145.
[15] ZHANG Y, PROENEA R, MAFFEI M, et al. Positional cloning of the mouse obese gene and its human homologue[J]. Nature,1994, 372(6505):425-432.
[16] WANG C Y, LIAO J K. A mouse model of diet-induced obesity and insulin resistance[J]. Methods in Molecular Biology, 2012,821:421-433.
[17] MONTGOMERY M K, HALLAHAN N L, BROWN S H, et al.Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding[J]. Diabetologia, 2013, 56(5):1129-1139.
[18] PEYOT M L, PEPIN E, LAMINTAGNE J, et al. Beta-cell failure in diet-induced obese mice stratified according to body weight gain:secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta-cell mass[J]. Diabetes, 2010,59(9):2178-2187.
[19] PETTERSSON U S, WALDEN T B, CARLSSON P O, et al. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue[J]. PLoS One, 2012, 7(9):e46057.
[20] VILLARROYA F, CEREIJO R, GAVALDA-NAVARRO A, et al.Inflammation of brown/beige adipose tissues in obesity and metabolic disease[J]. Journal of Internal Medicine, 2018, 284(5):492-504.
[21] LOWELL B B, S-SUSULIE V, HAMANN A, et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue[J]. Nature, 1993, 366(6457):740-742.
[22] DE LAS HERAS N, KLETT-MINGO M, BALLESTEROS S, et al.Chronic exercise improves mitochondrial function and insulin sensitivity in brown adipose tissue[J]. Frontiers in Physiology,2018, 9:1122.
[23] HALBAN P A, POLONSKY K S, BOWDEN D W, et al.β-cell failure in type 2 diabetes:postulated mechanisms and prospects for prevention and treatment[J]. Diabetes Care, 2014, 37(6):1751-1758.
[24] LENZEN S. The mechanisms of alloxan-and streptozotocininduced diabetes[J]. Diabetologia, 2008, 51(2):216-226.
[25] ASRAFUZZAMAN M, CAO Y, AFROZ R, et al. Animal models for assessing the impact of natural products on the aetiology and metabolic pathophysiology of type 2 diabetes[J]. Biomedicine&Pharmacotherapy, 2017, 89:1242-1251.
[26] VANKRIEKEN P P, DICKER A, ERIKSSON M, et al. Kinetics of functional beta cell mass decay in a diphtheria toxin receptor mouse model of diabetes[J]. Scientific Reports, 2017, 7:12440.
[27] JIMENEZ V, AYUSO E, MALLOL C, et al. In vivo genetic engineering of murine pancreatic beta cells mediated by singlestranded adeno-associated viral vectors of serotypes 6, 8 and 9[J].Diabetologia, 2011, 54(5):1075-1086.
[28] SAMUEL V T, SHULMAN G I. Mechanisms for insulin resistance:common threads and missing links[J]. Cell, 2012, 148(5):852-871.
[29] UNGER R H, CHERRINGTON A D. Glucagonocentric restruc turing of diabetes:a pathophysiologic and therapeutic makeover[J]. The Journal of Clinical Investigation, 2012, 122(1):4-12.
[30] FOLLO F, LA ROSA S, FINZI G, et al. Pancreatic islet of Langerhans’cytoarchitecture and ultrastructure in normal glu cose tolerance and in type 2 diabetes mellitus[J]. Diabetes, Obesity&Metabolism, 2018, 20(2):137-144.
[31] HONDA A, KOMIYA K, HARA A, et al. Normal pancreaticβ-cell function in mice with RIP-Cre-mediated inactivation of p62/SQSTM1[J]. Endocrine Journal, 2018, 65(1):83-89.
[32] WICKSTEED B, BRISSOVA M, YAN W, et al. Conditional gene targeting in mouse pancreaticβ-cells:analysis of ectopic Cre transgene expression in the brain[J]. Diabetes, 2010, 59(12):3090-3098.
[33] BROUWERS B, DE FAUDEUR G, OSIPOVICH A B, et al.Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression[J]. Cell Metabolism, 2014, 20(6):979-990.
[34] THORENS B, TARUSSIO D, MAESTRO M A, et al. Ins1Cre knock-in mice for beta cell-specific gene recombination[J]. Diabetologia, 2015, 58(3):558-565.
[35] ACKERMANN A M, ZHANG J, HELLER A, et al. High-fidelity Glucagon-CreER mouse line generated by CRISPRCas9 assisted gene targeting[J]. Molecular Metabolism, 2017, 6(3):236-244.
[36] SHI X, CHACKO S, LI F, et al. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity[J]. Molecular Metabolism, 2017, 6(11):1350-1359.
[37] SOEDLING H, HODSON D J, ADRIANSSENS A E, et al.Limited impact on glucose homeostasis of leptin receptor deletion from insulin-or proglucagon-expressing cells[J]. Molecular Metabolism, 2015, 4(9):619-630.
[38] ABEL E D, PERONI O, KIM J K, et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver[J]. Nature, 2001, 409(6821):729-733.
[39] GUILLAM M T, HUMMLER E, SCHAERER E, et al. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2[J]. Nature Genetics, 1997, 17(3):327-330.
[40] SONE H, SUZUKI H, TAKAHASHI A, et al. Disease model:hyperinsulinemia and insulin resistance:part A—targeted disruption of insulin signaling or glucose transpor[J]. Trends in Molecular Medicine, 2001, 7(8):320-322.
[41] DIEESLER S, JAN M, EMMENEGGER Y, et al. A systems genetics resource and analysis of sleep regulation in the mouse[J].PLoS Biology, 2018, 16(8):e2005750.
[42] ANDREUX P A, WILLIAMS E G, KOUTNIKOVA H, et al.Systems genetics of metabolism:the use of the BXD murine reference panel for multiscalar integration of traits[J]. Cell, 2012,150(6):1287-1299.
[43] CLAUSSNITZER M, DANKEL S N, KIM K H, et al. FTO obesity variant circuitry and adipocyte browning in humans[J]. The New England Journal of Medicine, 2015, 373(10):895-907.
[44] DA SILVA XAVIER G, BELLOMO E A, MCGINTY J A, et al.Animal models of GWAS-identified type 2 diabetes genes[J].Journal of Diabetes Research, 2013, 2013:906590.
[45] AZUSHIMA K, GURLEY S B, COFFMAN T M. Modelling diabetic nephropathy in mice[J]. Nature Reviews Nephrology, 2018,14(1):48-56.
[46] ZHAO H J, WANG S, CHENG H, et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice[J]. Journal of the American Society of Nephrology, 2006, 17(10):2664-2669.
[47] MOHAN S, REDDICK R L, MUSI N, et al. Diabetic eNOS knockout mice develop distinct macro-and microvascular complications[J]. Laboratory Investigation, 2015, 88(5):515-528.
[48] ZHANG M Z, WANG S, YANG S, et al. Role of blood pressure and the renin-angiotensin system in development of dia betic nephropathy(DN)in eNOS-/-db/db mice[J]. American Journal of Physiology:Renal Physiology, 2012, 302(4):F433-F438.
[49] HUDKINS K L, PICHAIWONG W, WIETECHA T, et al. BTBR ob/ob mutant mice model progressive diabetic nephropathy[J].Journal of the American Society of Nephrology, 2010, 21(9):1533-1542.
[50] KORZH V, GRUNWALD D. Nadine Dobrovolska觙a-Zavadska觙a and the dawn of developmental genetics[J]. Bioessays, 2001, 23(4):365-371.
[51] CLEE S M, NADLEER S T, ATTIE A D. Genetic and genomic studies of the BTBR ob/ob mouse model of type 2 diabetes[J].American Journal of Therapeutics, 2005, 12(6):491-498.
[52] MERSCHER-GOMEZ S, GUZMAN J, PEDIGO C E, et al.Cyclodextrin protects podocytes in diabetic kidney disease[J].Diabetes, 2013, 62(11):3817-3827.
[53] GEMBARDT F, BARTAUN C, JARZEBSKA N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension[J]. American Journal of Physiology:Renal Physiology, 2014, 307(3):F317-F325.
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