Cisplatin-Induced Rodent Model of Kidney Injury: Characteristics and Challenges

Table 1

Genetically altered mice used in the investigation of cisplatin nephrotoxicity.

		age
	background	sex	cisplatin
GEM model	(breeder)	N	dose	end	mortality	S	measured parameters	Ref.
		25-30g
	129/SV	male	10 mg/kg				BUN, Cr, Cr clearance, HO-1, p21mRNA
CYP2e1^−/−	(NIH)	N=10	ip	D3	nr	↓	and protein, TUNEL	[74]
Oct1^−/−		8-12wk				ns
Oct2^−/−	FVB	male	10 mg/kg			ns
Oct1/2/^−/−	(Taconic)	N=11	ip	D3	nr	↓	Histology, Cr, BUN, ALT↑, ALP↓	[35]
		6-10wk
	C57BL/6	male, female	15 mg/kg
GstP1/P2^−/−	(UK)	N=5-9	ip	D5	0%	↓	Cr, ATN, WBC	[75]
		11-15wk					D3:BUN, Cr, AST
Mate1^−/−		male	15 mg/kg				mortality
(pyrimethamine)	C57BL/6	N=6	ip	D6	100%	↑		[41]
Mdk^−/−	129SV	8-12wk	12 mg/kg	D7	nr	↓	↓BUN, TUNEL, histology, ≈leukocytes	[76]
		male	ip				infiltration (neutrophil, macrophages, Tcells),
		N=6					Bcl-2, KC protein, MCP-1, MIP-2
		8-10wk					Survival, histology, BUN, Cr, leukocyte
		male	15 mg/kg				infiltration, TUNEL, TNFα, ICAM1 mRNA,
PI3Kγ^−/−	C57BL/6	N=25	ip	D5	44%	↑	proteins, p-Akt, p-Bad	[77]
		10-12wk
	B6x129/SF2/J	male	20 mg/kg
E2F1^−/−	(Jax)	N=6	ip	D3	nr	↓	↓BUN, Cr, histology,	[78]
p53^−/−	nr	N=6	20 mg/kg
(pifithrin-α)	(Jax)		ip	D3	nr	↓	↓BUN, Cr, histology	[79]
p53^−/−	C57BL/6J	8-10 wk, male	30 mg/kg
(pifithrin-α)	(Jax)	N=22-29	ip	D3	nr	↓	↓BUN, Cr, histology	[80]
	C57BL/6	8-10wk, male	30 mg/kg
Bax^−/−	(Jax)	N=3-8	ip	D3	nr	↓	BUN, Cr, ATN, TUNEL, cytochrome C	[81]
							Histology, BUN, Cr, neutrophils infiltration,
	C57BL/6	8-10wk, male					TUNEL, Casp-1,-3,-8,-9 activity, IL-1β
Casp-1^−/−	(Japan)	N=4-15	30 mg/kg	D3	nr	↓		[82]
		8-15 wk, male					BUN, histology, TUNEL
p21-/-	nr	N=5-6	20 mg/kg	D3	30%	↑		[83]
HO-1^+/-		12-16wk	20 mg/kg			≈
HO-1^−/−	nr	N=8	ip	D3		↑	↓BW, ↑BUN	[84]
	C57BL/10Sn	6-8 wk		D3
C5^−/−	(Jax)	male				↓	BUN, Cr, histology, MDA, MPO,	[85]
	BALB/c	N=5-12	20 mg/kg				nitrotyrosine, TNF-α, IL-1β, ICAM-1, casp-3,8,9, STAT3, NF-κB
C5aR^−/−	(Jax)	SPF	ip			↓
	DBA/1lacJ x	3-4 months					BW, histology, BUN, Cr, Hct,
mPGES-1^−/−	C57BL/6 x	male	20 mg/kg				TNFα, IL-1β;
(celecoxib)	129/SV	N=6-16	ip	D3	nr	↓		[86]
TNFα^-/-		8-9 wk					Histology, BUN, leukocyte infiltration
(GM6001,	B6129SF2/J	male
Pentoxifylline	(Jax)	N=7	20 mg/kg	D3	nr	↓		[87]
	C57BL/6	8-10wk, male					Histology, BUN, Cr, neutrophil infiltration,
TLR4^−/−	(Jax)	N=4-7	20 mg/kg	D3	nr	↓	cytokines	[88]
				D1			Kidney: ↑neutrophils, CXCL1, CXCL2,
		8-10wk					≈CD4^+, ↓CD4^+CD25^+, Foxp3
		N=6-10
TLR9^−/−	C57BL/6		20 mg/kg	D3	nr	↑	Blood: ↑BUN; Kidney: ↑histology score	[72]
	C57BL/6	8-10 wks	15mg/kg				Blood: ≈BUN; Kidney: ≈histology score
Tcrd^−/−	(Jax)	♂, N=9	ip	D4	nr	ns		[67]
Asc^−/−	C57BL/6	8-10 wk, male	15mg/kg				Blood: ↓BUN;
TLR2^−/−	(Jax)	N=5	ip	D4	nr	↓	Kidney: ↓histology score, IL-17A, IL-1β	[67]
	C57BL/6	8-10 wk, male	15mg/kg				Blood: ↓BUN; Kidney: ↓histology score
Rorγt-/-	(Jax)	N=9	ip	D4	nr	↓		[67]
		8-10 wk,		D1			Kidney:↓neutrophils, ≈CD4^+ T cells, CXCL1,
IL-17A^−/−	C57BL/6	male	15mg/kg				CXCL2, CCL2, CCL5
(anti-IL-17A)	(Jax)	N=8	ip	D4	nr	↓	Blood: ↓BUN; Kidney: ↓histology score	[67]
	C57BL/6	8-10 wk, male					Histology, BUN, Cr,
IL-6 ^−/−	(Jax)	N=4-6	30 mg/kg	D3	nr	ns		[65]
		10-12wk,					↓Mortality,
	C57BL/6J	male					↑BUN	[89, 90]
IL-6^−/−	(Jax)	N=9-18	30 mg/kg	D8	47%	↓
		6-8 wk					Morality, Cr, histology, MPO,
nu/nu; B6.Cg-Foxn	C57BL/6	male					TNFα, IFN-γ,IL-1β, KC
(T-cell transfer)	(Jax)	N=3-14	40 mg/kg	D3	0%	↓		[69]
		6-8wk		D2	6%		Mortality, BUN, Cr, histology, macrophage
nu/nu; (CD4+CD25+Treg	BALB/c	male		D3	31%		infiltration (F4/80 positive cells), TNFα, IL-1β
transfer)	(South Korea)	N=16	40 mg/kg	D4	13%	↓		[70]
CD4^−/−	B6129S2	6-8 wk, male					↓Morality, Cr, histology
B6.129S2-Cd4tm1Mak	(Jax)	N=16	40 mg/kg	D3	38%	↓		[69]
		8-10wk					Blood: ↓Cr; Kidney: ↓histology score
CD4^−/−; CD4 tm1Mak	C57BL/6	male
GK1.5 monoclonal AB	(Jax)	N=	25 mg/kg	D3	nr	↓		[51]
		8-10wk	10 mg/kg				Blood: ≈BUN, Cr; Kidney: ≈caspase-3,
CD4^−/−; CD4 tm1Mak	C57BL/6	male	per week				TUNEL,≈ IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, CXCL1, TNFα, IFN-γ
GK1.5 monoclonal AB	(Jax)	N=10	for 4 wks	4wks	nr	ns		[91]
CD8^−/−	B6129S2	6-8 wk, male					Mortality, Cr, histology
B6.129S2-Cd8atm1Mak	(Jax)	N=16	40 mg/kg	D3	56%	↓		[69]
	C57BL/6	8-10wk, male					Blood: ↓Cr; Kidney:↓histology score,
CXCR2^−/−	(Jax)	N=4	25 mg/kg	D3	nr	↓	apoptosis	[51]
	C57BL/6 (wt)	8-10wks	12 mg/kg				Blood: ↓BUN, serum TNF; Kidney:
	(Jax)	N=7	ip	D4	0%	↓	↓histology score	[71]

A pharmacological inhibitor of particular gene/protein. IL-6 deficiency accelerates the development of nephrotoxicity at the early stage but resists the progress of systemic injury [89].
N: number; S: susceptibility to cisplatin toxicity; ip: intraperitoneally; D: day; ≈: ns; ↓: decrease; ↑: increase; BUN: blood urea nitrogen; Cr: serum creatinine; GFR: glomerular filtration rate; ATN: acute tubular necrosis; BW: body weight; WBC: white blood cells; Hct: hematocrit; TNFα: tumor necrosis factor alpha; IL: interleukin; IFNγ: interferon gamma; MCP-1: monocyte chemoattractant protein-1; HO-1: heme oxygenase-1; ICAM-1: intracellular adhesion molecule-1; TLR4: toll like receptor 4; COX: cyclooxygenase; Casp3: caspase 3; KC: keratinocyte-derived chemokine; MPO: myeloperoxidase; SOD: superoxide dismutase; CAT: catalase; GSH: glutathione; GPx: glutathione peroxidase; GR: glutathione reductase; GST: glutathione S transferase; MDA: malondialdehyde; ALT: alanine transaminase; AST: aspartate transaminase; ALP: alkaline phosphatase; Cas3: caspase 3; Cas9: caspase 9; CXCL: chemokine (C-X-C motif) ligand; CCL: chemokine (C-C motif) ligand.