J Korean Med Sci.  2010 Apr;25(4):557-563. 10.3346/jkms.2010.25.4.557.

IL-10 Mediates Rosiglitazone-Induced Kidney Protection in Cisplatin Nephrotoxicity

• Kim MG
• Yang HN
• Kim HW
• Jo SK
• Cho WY
• Kim HK

• KMID: 1792925
• DOI: http://doi.org/10.3346/jkms.2010.25.4.557

Abstract

Cisplatin, a major anti-neoplastic drug, is known to be nephrotoxic and inflammation-inducing. A peroxisome proliferator-activated receptor gamma agonist, regulating lipid metabolism, has known to have anti-inflammatory effect, but the protection mechanisms in various kidney injuries are not fully understood. The purpose of this study was to examine the reno-protective effect of rosiglitazone on cisplatin nephrotoxicity in mice focusing on inflammation and apoptosis. Male BALB/c mice were pretreated with rosiglitazone (10 mg/kg) or vehicle through daily intraperitoneal injection for 3 days and then were given a single injection of cisplatin (20 mg/kg). Cisplatin induced a significant rise in blood urea nitrogen and creatinine levels, and tubular cell damage with marked tissue inflammation. Tissue cytokines and chemokines measured by a cytometric bead array showed increased TNF-alpha, IL-6, MCP-1, and IFN-gamma levels, while IL-10, an anti-inflammatory cytokine, was significantly decreased by cisplatin treatment. However, rosiglitazone pretreatment substantially reversed the depressed IL-10 level with simultaneous suppression of proinflammatory cytokines and chemokines. This tissue cytokine and chemokine milieu was associated with marked attenuation of kidney injury elicited by cisplatin. These findings suggest that the rosiglitazone-mediated renoprotective effect in cisplatin nephrotoxicity of mice is partially mediated by upregulation of anti-inflammatory IL-10 production.

Keyword

Cisplatin Nephrotoxicity; Interleukin-10; PPAR Gamma Agonist

MeSH Terms

Acute Kidney Injury/*chemically induced
Animals
Apoptosis/physiology
Caspases/metabolism
Chemokines/metabolism
Cisplatin/*toxicity
Cytokines/metabolism
Enzyme Activation
Hypoglycemic Agents/*pharmacology
Interleukin-10/*metabolism/pharmacology
Kidney/*drug effects/metabolism/pathology
Male
Mice
Mice, Inbred BALB C
PPAR gamma/metabolism
Thiazolidinediones/*pharmacology
Chemokines
Cytokines
Hypoglycemic Agents
PPAR gamma
Thiazolidinediones
Interleukin-10
Cisplatin
Caspases

Figure

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  Fig. 1 Effect of rosiglitazone on renal function in cisplatin-induced ARF in mice. Vehicle (0.1% DMSO) or rosiglitazone (rosi) were injected intraperitoneally for 3 days before cisplatin (cis) administration. Blood urea nitrogen (BUN) and creatinine (Cr) were measured at 4, 24, and 72 hr (n=5 animals per group). *P<0.05 vs. control, †P<0.05 vs. vehicle+cisplatin. C, control; R, rosiglitazone.

• 

  Fig. 2 Effect of rosiglitazone on renal histology in cisplatin-induced renal injury in mice. Renal histology was examined at 72 hr after cisplatin injection. Semiquantitative assessment of renal damage was scored as described in the Method section. (A) Vehicle+cisplatin (vehicle/cis), (B) Rosiglitazone+cisplatin (rosi/cis), (C) Semiquantitative histologic injury score. (A, B) Periodic acid-Schiff (PAS) ×200 (n=9 animals per group). *P<0.05 vs. vehicle+cisplatin.

• 

  Fig. 3 Effect of rosiglitazone on cytokines/chemokine expression in cisplatin-induced renal injury in mice. Inflammatory cytokines and MCP-1 was quantified at 24 and 48 hr after injection of vehicle+cisplatin (vehicle/cis) or rosiglitazone+cisplatin (rosi/cis) by cytometric bead array. In each experiment, data are presented as mean±SE (n=9 animals per group). *P<0.05 vs. control; †P<0.05 vs. vehicle+cisplatin. C, control; R, rosiglitazone.

• 

  Fig. 4 Effect of rosiglitazone on esterase positive cells infiltration in cisplatin-induced renal injury in mice. Eight to ten ×200 fields were counted and mean numbers of esterase positive leukocytes were compared at 72 hr after cisplatin administration. (A) Vehicle+cisplatin (vehicle/cis), (B) Rosiglitazone+cisplatin (rosi/cis), (C) Mean number of esterase positive cells (n=9 animals per group). *P<0.05 vs. vehicle+cisplatin.

• 

  Fig. 5 Effect of rosiglitazone on F4/80 positive cells infiltration in cisplatin-induced renal injury in mice. Eight to ten ×200 fields were counted and mean numbers of F4/80 positive leukocytes were compared at 72 hr after cisplatin administration. (A) Vehicle+cisplatin (vehicle/cis), (B) Rosiglitazone+cisplatin (rosi/cis), (C) Mean numbers of F4/80 positive cells (n=9 animals per group). *P<0.05 vs. vehicle+cisplatin.

• 

  Fig. 6 Effect of rosiglitazone on the activation of caspases in cisplatin-induced renal injury in mice. Tissue caspase activities were measured at 4, 24, and 72 hr and were expressed as percent increase compared to saline treated control group. (A) Caspase 3 activity, (B) Caspase 8 activity, (C) Caspase 9 activity (n=9 animals per group). *P<0.05 vs. control, †P<0.05 vs. vehicle+cisplatin.

• 

  Fig. 7 Effect of rosiglitazone on apoptosis in cisplatin-induced renal injury in mice. Detection of apoptosis was done at 48 hr after cisplatin administration. (A) Vehicle+cisplatin (vehicle/cis), (B) Rosiglitazone+cisplatin (rosi/cis), (C) Mean numbers of TUNEL positive cells were counted in eight to ten high power field. (A, B) TUNEL stain ×200 (n=9 animals per group). *P<0.05 vs. control, †P<0.05 vs. vehicle+cisplatin.

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