Translation Animal Models of Diabetic Kidney Disease: Biochemical and Histological Phenotypes, Advantages and Limitations

Figures & data

Table 1 Biochemical and Histological Phenotypes in Translation Animal Models of T1D-DKD

Type	Animal Model	Treatment	Strain	Ob	HBS	HBP	HTC	HC	PRO	Early Glomerular Pathology			Advanced Glomerular Pathology		TIF	GFR (#)	Ref.
										Mesangial Matrix Expansion	GBM Thickening	Fibrosis or Mild Sclerosis	Nodular/Diffuse Sclerosis	Arterial Hyalinosis
Chemical	Mice	STZ	B6	-	+	-	NA	NA	+	+	+	-	- / -	-	-	-	[13,14,18,19]
			DBA/2	-	+	-	NA	NA	+	+^b	+	+	- / -	+	-	-
			CD1	-	+	-	+	-	+ ^a	+^b	+	+	- / +	-	+	+
			129Sv	-	+	+	NA	NA	±	+	+	-	- / -	-	-	-
			KK/HIJ	-	+	-	NA	NA	+	+	+	+	- / -	+	-	-
	Rats	STZ	SD, Wistar	-	+	-	NA	NA	+	±	±	-	- / -	-	-	-	[24–28]
	Zebrafish	STZ		NA	+	NA	NA	NA	-	NA	+	NA	NA	NA	NA	NA	[15]
Surgical + Chemical	Mice	UNx + STZ	B6	-	+	-	NA	NA	+	+	+	+	- / -	-	+	-	[38]
	Rats	UNx + STZ	SD, Wistar	-	+	-	NA	NA	+	+	+	+	- / -	-	-	-	[40,41]
			SHR	-	+	+	+	+	+	+	+	+	- / -	-	NA	NA	[42]
Genetic	Akita mice		B6	-	+	+	-	-	+	+	-	-	- / -	-	NA	-	[44,47]
			DBA/2, 129/SvEv	-	+	+	NA	NA	+	+	-	-	- / -	-	NA	-	[44]
			KK/Ta	-	+	+	+	+	+	+	+	+	- / -	+	+	+	[46,47]
		Akita KO	Balb/c	-	+	+	NA	NA	+	+	+	+	- / -	-	-	+	[48]
	OVE26 mice		FVB	-	+	+	NA	NA	+^a	+^b	+	+	+ / -	-	+	+^b	[50,51]

Notes: +, positive; -, negative; ±, weakly positive or inconsistent results; NA, not available; a, > 10-fold; b, > 50%; #, vs normal value.

Abbreviations: T1D-DKD, type 1 diabetic kidney disease; Ob, Obesity; HBS, high blood sugar; HBP, high blood pressure; HTG, high triglycerides; HC, high cholesterol; PRO, Proteinuria; GMB, glomerular basement membrane; TIF, tubulointerstitial fibrosis; GFR, glomerular filtration rate; Ref., references; KO, knockout; STZ, streptozotocin; UNx, uninephrectomy.

Table 2 Biochemical and Histological Phenotypes in Translation Animal Models of T2D-DKD

Type	Animal Model	Treatment	Strain	Ob	HBS	HBP	HTC	HC	PRO	Early Glomerular Pathology			Advanced Glomerular Pathology		TIF	GFR (#)	Ref.
										Mesangial Matrix Expansion	GBM Thickening	Fibrosis or Mild Sclerosis	Nodular/Diffuse Sclerosis	Arterial Hyalinosis
Chemical	Mice	STZ + NAD	B6	-	+	NA	NA	NA	+	+	+	+	- / -	-	+	-	[53,54]
	Rats	STZ + NAD	Wistar	-	+	NA	±	±	+	+	+	+	- / -	-	+	-	[55–61]
Dietary	Mice	HFD	B6	+	+	+	+	+	+	+	+	-	- / -	-	-	-	[64,67–69]
	Chinese Bama minipigs	HsuHF or HFHsuHC		+	±	NA	+	+	+	+	+	+	- / -	-	+	-	[71,72]
Chemical + Dietary	Mice	STZ + HFD	B6	±	+	NA	+	+	+	+	+	+	- / -	-	+	-	[80–87]
	Rats	STZ + HFD	SD, Wistar	±	+	NA	+	±	+	+	+	+	- / -	-	-	-	[76–79]
Surgical + Chemical + Dietary	Mice	UNx + STZ + HFD	B6	NA	+	NA	NA	NA	+	+	+	+	- / -	+	+	-	[92]
	Rats	UNx + STZ + HFD or UNx + STZ + NAD + HFD	SD, Wistar	±	+	±	+	+	+^a	+	+	+	- / ±	-	±	-	[32,91]
Spontaneous	OLETF rats		OLETF	+	+	±	+	+	+^a	+	+	+	+ / -	-	+	-	[93–96]
	GK rats		GK	-	+	-	-	-	±	+	+	+	- / -	-	+	-	[103–105]
		DOCA or Angǁ + HSaD		-	+	+	-	-	+	+	+	+	- / -	-	+	-	[103,106]
		HFD		-	+	-	-	-	±	+	+	+	- / -	-	+	-	[107]
Genetic	ob/ob mice		BTBR	+	+	-	+	+	+^a	+^b	+	+	± / +	+	±	-	[110]
		HPD		+	+	-	+	+	+^a	+^b	+	+	± / +	+	+	-	[111]
	db/db mice		BKS	+	+	-	+	+	+^a	+	+	-	- / -	±	-	-	[116–119,122]
		HPD		+	+	NA	+	+	+^a	+	+	+	- / -	±	+	-	[121]
		UNx		+	+	-	+	+	+^a	+	+	+	- / -	-	+	+	[122,123]
			DBA/2J	+	+	NA	+	+	+^a	+	+	+	- / -	-	-	-	[117]
			FVB	+	+	NA	+	+	+	+	+	+	- / -	-	+	-	[124]
			CD1	+	+	-	NA	NA	+^a	+	+	+	-/+	-	+	+	[115]
	ZDF rats		ZDF	+	+	±	+	+	+^a	+	+	+	- / -	-	+	-	[125,127–130]
		HFD		+	+	±	+	+	+^a	+	+	+	- / -	-	+	-	[130,131]
	ZSF1 rats		ZDF × SHHF	+	+	+	+	+	+^a	+	+	+	- / ±	+	+	+^b	[133–135]
	KKA^y/Ta mice		KK/Ta	+	+	-	+	+	+	+	+	+	- / -	-	+	-	[138–140]
		HFD		+	+	-	+	+	+	+	+	+	- / -	-	+	-	[138]
	T2DN rats		T2DN/Mcwi	-	+	-	+	+	+^a	+	+	+	+ / +	+	+	+^b	[142–144]

Notes: +, positive; -, negative; ±, weakly positive or inconsistent results; NA, not available; a, > 10-fold; b, > 50%; #, vs normal value.

Abbreviations: T2D-DKD, type 2 diabetic kidney disease; Ob, Obesity; HBS, high blood sugar; HBP, high blood pressure; HTG, high triglycerides; HC, high cholesterol; PRO, Proteinuria; GMB, glomerular basement membrane; TIF, tubulointerstitial fibrosis; GFR, glomerular filtration rate; Ref., references; STZ, streptozotocin; UNx, uninephrectomy; NAD, nicotinamide; HFD, high-fat diet; HsuHF, high-sugar-high-fat diet; HFHsuHC, high-fat-high-sugar-high-cholesterol diet; Angǁ, angiotensinǁ; DOCA, deoxycorticosterone acetate; HSaD, high-salt diet; HPD, high-protein diet.

Table 3 Biochemical and Histological Phenotypes in Complication Models of DKD and NADKD

Type	Animal Model	Treatment	Strain	Ob	HBS	HBP	HTC	HC	PRO	Early Glomerular Pathology			Advanced Glomerular Pathology		TIF	GFR (#)	Ref.
										Mesangial Matrix Expansion	GBM Thickening	Fibrosis or Mild Sclerosis	Nodular/Diffuse Sclerosis	Arterial Hyalinosis
DKD × HBP	eNOS^−/−/db/db mice	eNOSKO	BKS	+	+	+	-	+	+^a	+	+	+	+ / +	±	±	+^b	[152,153,162]
DKD × Atherosclerosis	IDOL-AAV-DJ/8-ob/ob mice	HFHC	BTBR (ob/ob)	+	+	NA	+	+	+^a	+^b	+	+	± / +	+	±	-	[166]
NADKD × Atherosclerosis	HFD-ApoE^−/− mice	HFD	B6	+	+	NA	+	+	±	+	NA	+	- / -	-	+	-	[169]

Notes: +, positive; -, negative; ±, weakly positive or inconsistent results; NA, not available; a, > 10-fold; b, > 50%; #, vs normal value.

Abbreviations: DKD, diabetic kidney disease; NADKD, normoalbuminuric diabetic kidney disease; Ob, Obesity; HBS, high blood sugar; HBP, high blood pressure; HTG, high triglycerides; HC, high cholesterol; PRO, Proteinuria; GMB, glomerular basement membrane; TIF, tubulointerstitial fibrosis; GFR, glomerular filtration rate; Ref., references; KO, knockout; HFD, high-fat diet; HFHC high-fat-high-cholesterol diet.

Figure 1 Induction procedures for rodent models of T1D-DKD.

Abbreviations: T1D-DKD, type 1 diabetic kidney disease; STZ, streptozotocin; UNx, uninephrectomy; i.p. intraperitoneal injection.

Figure 2 Induction procedures for rodent models of T2D-DKD.

Abbreviations: T2D-DKD, type 2 diabetic kidney disease; NAD, nicotinamide; STZ, streptozotocin; UNx, uninephrectomy; i.p. intraperitoneal injection; HFD, high-fat diet; HsuHF, high-sugar-high-fat diet; HFHsuHC, high-fat-high-sugar-high-cholesterol diet.

Sugimoto H, Grahovac G, Zeisberg M, Kalluri R. Renal fibrosis and glomerulosclerosis in a new mouse model of diabetic nephropathy and its regression by bone morphogenic protein-7 and advanced glycation end product inhibitors. Diabetes. 2007;56(7):1825–1833. doi:10.2337/db06-1226

 PubMed Web of Science ®Google Scholar

Tesch GH, Allen TJ. Rodent models of streptozotocin-induced diabetic nephropathy. Nephrology. 2007;12(3):261–266. doi:10.1111/j.1440-1797.2007.00796.x

 PubMed Web of Science ®Google Scholar

Zheng C, Huang L, Luo W, et al. Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice. Cell Death Dis. 2019;10(11):848. doi:10.1038/s41419-019-2085-0

 PubMedGoogle Scholar

Liu XQ, Jiang L, Li YY, et al. Wogonin protects glomerular podocytes by targeting Bcl-2-mediated autophagy and apoptosis in diabetic kidney disease. Acta Pharmacol Sin. 2022;43(1):96–110. doi:10.1038/s41401-021-00721-5

 PubMed Web of Science ®Google Scholar

Betz B, Conway BR. An update on the use of animal models in diabetic nephropathy research. Curr Diab Rep. 2016;16(2):18. doi:10.1007/s11892-015-0706-2

 PubMed Web of Science ®Google Scholar

Uil M, Scantlebery AML, Butter LM, et al. Author correction: combining streptozotocin and unilateral nephrectomy is an effective method for inducing experimental diabetic nephropathy in the ‘resistant’ C57Bl/6J mouse strain. Sci Rep. 2019;9(1):3425. doi:10.1038/s41598-018-38075-4

 PubMedGoogle Scholar

Mao ZM, Shen SM, Wan YG, et al. Huangkui capsule attenuates renal fibrosis in diabetic nephropathy rats through regulating oxidative stress and p38MAPK/Akt pathways, compared to α-lipoic acid. J Ethnopharmacol. 2015;173:256–265. doi:10.1016/j.jep.2015.07.036

 PubMed Web of Science ®Google Scholar

Liu BC, Huang HQ, Luo DD, Ma KL, Liu DG, Liu H. Connective tissue growth factor is associated with the early renal hypertrophy in uninephrectomized diabetic rats. Chin Med J. 2006;119(12):1010–1016.

 PubMed Web of Science ®Google Scholar

Inada Y, Murakami M, Tazawa S, Akahane M. KRH-594, a new angiotensin AT1 receptor antagonist, ameliorates nephropathy and hyperlipidaemia in diabetic spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 2000;27(4):270–276. doi:10.1046/j.1440-1681.2000.03235.x

 PubMed Web of Science ®Google Scholar

Gurley SB, Mach CL, Stegbauer J, et al. Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice. Am J Physiol Renal Physiol. 2010;298(3):F788–F795. doi:10.1152/ajprenal.90515.2008

 PubMed Web of Science ®Google Scholar

Fujita H, Fujishima H, Chida S, et al. Reduction of renal superoxide dismutase in progressive diabetic nephropathy. J Am Soc Nephrol. 2009;20(6):1303–1313. doi:10.1681/asn.2008080844

 PubMed Web of Science ®Google Scholar

Jerums G, Premaratne E, Panagiotopoulos S, MacIsaac RJ. The clinical significance of hyperfiltration in diabetes. Diabetologia. 2010;53(10):2093–2104. doi:10.1007/s00125-010-1794-9

 PubMed Web of Science ®Google Scholar

Yu L, Su Y, Paueksakon P, et al. Integrin α1/Akita double-knockout mice on a Balb/c background develop advanced features of human diabetic nephropathy. Kidney Int. 2012;81(11):1086–1097. doi:10.1038/ki.2011.474

 PubMed Web of Science ®Google Scholar

Zheng S, Noonan WT, Metreveli NS, et al. Development of late-stage diabetic nephropathy in OVE26 diabetic mice. Diabetes. 2004;53(12):3248–3257. doi:10.2337/diabetes.53.12.3248

 PubMed Web of Science ®Google Scholar

Zheng S, Huang Y, Yang L, Chen T, Xu J, Epstein PN. Uninephrectomy of diabetic OVE26 mice greatly accelerates albuminuria, fibrosis, inflammatory cell infiltration and changes in gene expression. Nephron Exp Nephrol. 2011;119(1):e21–e32. doi:10.1159/000327586

 PubMedGoogle Scholar

Hsu JD, Wu CC, Hung CN, Wang CJ, Huang HP. Myrciaria cauliflora extract improves diabetic nephropathy via suppression of oxidative stress and inflammation in streptozotocin-nicotinamide mice. J Food Drug Anal. 2016;24(4):730–737. doi:10.1016/j.jfda.2016.03.009

 PubMed Web of Science ®Google Scholar

Perez Gutierrez RM, Garcia Campoy AH, Paredes Carrera SP, Muniz Ramirez A, Mota Flores JM, Flores Valle SO. 3’-O-beta-d-glucopyranosyl-alpha,4,2’,4’,6’-pentahydroxy-dihydrochalcone, from bark of eysenhardtia polystachya prevents diabetic nephropathy via inhibiting protein glycation in STZ-nicotinamide induced diabetic mice. Molecules. 2019;24(7). doi:10.3390/molecules24071214

 PubMed Web of Science ®Google Scholar

Lee ES, Kwon MH, Kim HM, et al. Dibenzoylmethane ameliorates lipid-induced inflammation and oxidative injury in diabetic nephropathy. J Endocrinol. 2019;240(2):169–179. doi:10.1530/JOE-18-0206

 PubMed Web of Science ®Google Scholar

Liu Y, Wang Z, Yin W, et al. Severe insulin resistance and moderate glomerulosclerosis in a minipig model induced by high-fat/ high-sucrose/ high-cholesterol diet. Exp Anim. 2007;56(1):11–20. doi:10.1538/expanim.56.11

 PubMed Web of Science ®Google Scholar

Liu Y, Li H, Wang S, Yin W, Wang Z. Ibrolipim attenuates early-stage nephropathy in diet-induced diabetic minipigs: focus on oxidative stress and fibrogenesis. Biomed Pharmacother. 2020;129:110321. doi:10.1016/j.biopha.2020.110321

 PubMed Web of Science ®Google Scholar

Dusabimana T, Park EJ, Je J, et al. Geniposide improves diabetic nephropathy by enhancing ULK1-mediated autophagy and reducing oxidative stress through AMPK activation. Int J Mol Sci. 2021;22(4). doi:10.3390/ijms22041651

 Web of Science ®Google Scholar

Bayrasheva VK, Babenko AY, Dobronravov VA, et al. Uninephrectomized high-fat-fed nicotinamide-streptozotocin-induced diabetic rats: a model for the investigation of diabetic nephropathy in type 2 diabetes. J Diabetes Res. 2016;2016:8317850. doi:10.1155/2016/8317850

 PubMed Web of Science ®Google Scholar

Sugano M, Yamato H, Hayashi T, et al. High-fat diet in low-dose-streptozotocin-treated heminephrectomized rats induces all features of human type 2 diabetic nephropathy: a new rat model of diabetic nephropathy. Nutr Metab Cardiovasc Dis. 2006;16(7):477–484. doi:10.1016/j.numecd.2005.08.007

 PubMed Web of Science ®Google Scholar

Janssen U, Riley SG, Vassiliadou A, Floege J, Phillips AO. Hypertension superimposed on type II diabetes in Goto Kakizaki rats induces progressive nephropathy. Kidney Int. 2003;63(6):2162–2170. doi:10.1046/j.1523-1755.2003.00007.x

 PubMed Web of Science ®Google Scholar

Olearczyk JJ, Quigley JE, Mitchell BC, et al. Administration of a substituted adamantyl urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto–Kakizaki rats. Clin Sci. 2009;116(1):61–70. doi:10.1042/cs20080039

 Web of Science ®Google Scholar

Kuwabara WMT, Panveloski-Costa AC, Yokota CNF, et al. Comparison of Goto-Kakizaki rats and high fat diet-induced obese rats: are they reliable models to study Type 2 diabetes mellitus? PLoS One. 2017;12(12):e0189622. doi:10.1371/journal.pone.0189622

 PubMed Web of Science ®Google Scholar

Hudkins KL, Pichaiwong W, Wietecha T, et al. BTBR Ob/Ob mutant mice model progressive diabetic nephropathy. J Am Soc Nephrol. 2010;21(9):1533–1542. doi:10.1681/asn.2009121290

 PubMed Web of Science ®Google Scholar

Björnson Granqvist A, Ericsson A, Sanchez J, et al. High-protein diet accelerates diabetes and kidney disease in the BTBR ob/ob mouse. Am J Physiol Renal Physiol. 2020;318(3):F763–F771. doi:10.1152/ajprenal.00484.2019

 PubMed Web of Science ®Google Scholar

Maekawa M, Maekawa T, Sasase T, et al. Pathophysiological analysis of uninephrectomized db/db mice as a model of severe diabetic kidney disease. Physiol Res. 2022;71(2):209–217. doi:10.33549/physiolres.934784

 PubMed Web of Science ®Google Scholar

Nørgaard SA, Briand F, Sand FW, et al. Nephropathy in diabetic db/db mice is accelerated by high protein diet and improved by the SGLT2 inhibitor dapagliflozin. Eur J Pharmacol. 2019;860:172537. doi:10.1016/j.ejphar.2019.172537

 PubMed Web of Science ®Google Scholar

Aibara Y, Nakashima A, Kawano KI, et al. Daily low-intensity pulsed ultrasound ameliorates renal fibrosis and inflammation in experimental hypertensive and diabetic nephropathy. Hypertension. 2020;76(6):1906–1914. doi:10.1161/hypertensionaha.120.15237

 PubMed Web of Science ®Google Scholar

Østergaard MV, Pinto V, Stevenson K, Worm J, Fink LN, Coward RJ. DBA2J db/db mice are susceptible to early albuminuria and glomerulosclerosis that correlate with systemic insulin resistance. Am J Physiol Renal Physiol. 2017;312(2):F312–F321. doi:10.1152/ajprenal.00451.2016

 PubMed Web of Science ®Google Scholar

Wang Z, Jiang T, Li J, et al. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes. 2005;54(8):2328–2335. doi:10.2337/diabetes.54.8.2328

 PubMed Web of Science ®Google Scholar

Mizunuma Y, Kanasaki K, Nitta K, et al. CD-1(db/db) mice: a novel type 2 diabetic mouse model with progressive kidney fibrosis. J Diabetes Investig. 2020;11(6):1470–1481. doi:10.1111/jdi.13311

 PubMed Web of Science ®Google Scholar

Vora JP, Zimsen SM, Houghton DC, Anderson S. Evolution of metabolic and renal changes in the ZDF/Drt-fa rat model of type II diabetes. J Am Soc Nephrol. 1996;7(1):113–117. doi:10.1681/asn.V71113

 PubMed Web of Science ®Google Scholar

Kundu A, Gali S, Sharma S, et al. Tenovin-1 ameliorates renal fibrosis in high-fat-diet-induced diabetic nephropathy via antioxidant and anti-inflammatory pathways. Antioxidants. 2022;11(9). doi:10.3390/antiox11091812

 Web of Science ®Google Scholar

Pugsley MK, Brooks MB, Fishman CE, et al. Use of the ZDF rat to model dietary fat induced hypercoagulability is limited by progressive and fatal nephropathy. J Pharmacol Toxicol Methods. 2021;107:106933. doi:10.1016/j.vascn.2020.106933

 PubMed Web of Science ®Google Scholar

Liu Y, Huang H, Gao R, Dynamic Phenotypes LY. Molecular mechanisms to understand the pathogenesis of diabetic nephropathy in two widely used animal models of type 2 diabetes mellitus. Front Cell Dev Biol. 2020;8:172. doi:10.3389/fcell.2020.00172

 PubMed Web of Science ®Google Scholar

Zhao HJ, Wang S, Cheng H, et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol. 2006;17(10):2664–2669. doi:10.1681/asn.2006070798

 PubMed Web of Science ®Google Scholar

Mohan S, Reddick RL, Musi N, et al. Diabetic eNOS knockout mice develop distinct macro- and microvascular complications. Lab Invest. 2008;88(5):515–528. doi:10.1038/labinvest.2008.23

 PubMed Web of Science ®Google Scholar

Li Y, Chung S, Li Z, et al. Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control. JCI Insight. 2018;3(10). doi:10.1172/jci.insight.120365

 Web of Science ®Google Scholar

Bornfeldt KE, Kramer F, Batorsky A, et al. A novel type 2 diabetes mouse model of combined diabetic kidney disease and atherosclerosis. Am J Pathol. 2018;188(2):343–352. doi:10.1016/j.ajpath.2017.10.012

 PubMed Web of Science ®Google Scholar

Tomita I, Kume S, Sugahara S, et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab. 2020;32(3):404–419.e6. doi:10.1016/j.cmet.2020.06.020

 PubMed Web of Science ®Google Scholar