Pathophysiology of Cisplatin-Induced Acute Kidney Injury

Table 2

Pathophysiological pathways implicated in cisplatin-induced AKI and their corresponding in vivo protective models and molecules.

Pathophysiological pathway	Protective model/molecule	Effect	References
Apoptosis	Pifithrin	p53 inhibition—decreased apoptosis	[38]
	p53 knockout mice	p53 inhibition—decreased apoptosis	[38]
	Bax knockout mice	Bax inhibition—decreased apoptosis	[24]
	SIRT-1 overexpression	Deacetylation of p53—decreased apoptosis	[43]
	Resveratrol	SIRT-1 activator—decreased apoptosis	[44]
	Taurine transporter gene (TauT) transgenic mice	p53 inhibition—decreased apoptosis	[134]
Autophagy	Rapamycin	Induction of autophagy	[53]
ERK pathway	U0126	MEK-ERK inhibition	[27, 66]
p38 MAPK pathway	SKF-86002	p38 MAPK inhibition	[67]
Protein kinase C gamma pathway	PKCδ knockout model	Decreased apoptosis	[135]
	Rottlerin	PKCδ inhibition—decreased apoptosis	[135]
PPAR pathway	WY-14643 (PPAR ligand-fibrate)	PPAR activation	[136]
	PPAR transgenic mice	Increased PPAR activity	[76]
Oxidative stress	N-Acetylcysteine	Antioxidant	[128]
	Dimethylthiourea	Hydroxyl radical scavenging	[67, 68, 125, 127]
	Dimethyl sulfoxide	Hydroxyl radical scavenger	[125]
	b-Lapachone	NQO1 activator	[137]
	Amifostine	Antioxidant	[122, 123]
	Sodium thiosulfate	Antioxidant	[121]
	Vitamins C and E	Antioxidant	[129]
Cell cycle	E2F1 knockout mice	Decreased apoptosis	[138]
	Purvalanol	Cdk2 inhibitor—decreased apoptosis	[57]
	Sodium arsenite	p27 induction—decreased apoptosis	[60]
Mitochondrial metabolism	MDIVI-1	Dynamin-related protein-1 inhibition	[139]
	PKG-1 overexpressing transgenic mice	Improvement of mitochondrial functions—decreased apoptosis	[140]
	Sildenafil	PKG-1 activation	[140]
Iron metabolism	Cytochrome P450-2E1-null mice	Cytochrome P-450 inhibition	[120]
	Piperonyl butoxide	Cytochrome P-450 inhibition	[119]
	Deferoxamine	Iron chelation	[125]
Inflammation	GM6001	TNF-alpha inhibition	[80]
	TNF-alpha neutralizing antibody	TNF-alpha inhibition	[80]
	TNF-alpha knockout mice	TNF-alpha inhibition	[80]
	Salicylates	TNF-alpha inhibition	[82]
	Pentoxifylline	TNF-alpha inhibition	[83]
	Caspase-1 knockout	Decreased inflammation and apoptosis	[46]
	Anti-ICAM-1 (CD54)	Decreased neutrophil infiltration	[99]
	TLR4 knockout mice model	Decreased inflammation	[98]
	CXCR-2 knockout mice	Decreased inflammation	[88]
	Soluble ST2	Decreased inflammation, CD4+ T cell infiltration, and apoptosis	[88]
Prostaglandin metabolism	Microsomal prostaglandin E synthase-1 knockout mice	Decreased inflammation	[141]
	Celecoxib	COX-2 inhibition	[141]
T cells	T cell—deficient, CD4 and CD8 knockout models	Decreased inflammation	[81]
	Anti-Tim-1 antibodies	Decreased inflammation and apoptosis	[103]
	CD4+CD25+ Treg cells	Decreased inflammation and apoptosis	[106]
Mast cells	Mast cell-deficient mice model (KitW-sh/W-sh)	Decreased leukocyte infiltration and inflammation	[112]
	Sodium chromoglycate	Mast cell stabilization	[112]
Glucagon-like; peptide-1 (GLP-1)	Exendin-4	GLP-1 receptor agonist—decreased apoptosis	[142]
	Alogliptin	Dipeptidyl peptidase-4 inhibition—decreased apoptosis	[142]
Klotho metabolism	Transgenic Klotho overexpressing (Tg-Kl) mice	Decreased apoptosis and decreased uptake of cisplatin	[143]
Metalloproteinase metabolism	Actinonin	Meprin A inhibitor	[144]
Poly-ADP-ribose; polymerase-1 metabolism	PJ-34	PARP1 inhibition—decreased inflammation	[96]
Regeneration	Erythropoietin	Decreased apoptosis and increased mobilization of BM cells	[145–147]
	Granulocyte colony stimulating factor	Increased mobilization of BM cells	[148]
	Mesenchymal stem cells	Increased regeneration, decreased apoptosis	[149–154]

Anti-ICAM-1: anti-intercellular adhesion molecule-1, anti-TIM1: anti-T cell immunoglobulin mucin 1, BM: bone marrow, COX-2: cyclooxygenase-2, Cdk2: cyclin-dependent kinase-2, ERK: extracellular signal-regulated kinases, GLP-1: glucagon-like peptide-1, MAPK: mitogen-activated protein kinase, NQO1: NAD(P) H: quinone oxidoreductase 1, PARP-1: poly-ADP-ribose polymerase-1, PKC: protein kinase C, PKG-1: protein kinase G, PPAR: peroxisome proliferator-activated receptor, TLR-4: toll-like receptor 4, and TNF-alpha: tumor necrosis factor-alpha.