Renal fibrosis due to multiple cisplatin treatment is exacerbated by kinin B1 receptor antagonism

Cisplatin is a widely used chemotherapeutic drug, but its side effects are a major limiting factor. Nephrotoxicity occurs in one third of patients undergoing cisplatin treatment. The acute tubular injury caused by cisplatin often leads to a defective repair process, which translates into chronic renal disorders. In this way, cisplatin affects tubular cells, and maladaptive tubules regeneration will ultimately result in tubulointerstitial fibrosis. Kinins are well known for being important peptides in the regulation of inflammatory stimuli, and kinin B1 receptor deficiency and antagonism have been shown to be beneficial against acute cisplatin nephrotoxicity. This study aimed to analyze the effects of kinin B1 receptor deletion and antagonism against repeated cisplatin-induced chronic renal dysfunction and fibrosis. Both the deletion and the antagonism of B1 receptor exacerbated cisplatin-induced chronic renal dysfunction. Moreover, the inhibition of B1 receptor increased tubular injury and tubulointerstitial fibrosis after repeated treatment with cisplatin. The balance between M1/M2 macrophage polarization plays an important role in renal fibrosis. Kinin B1 receptor antagonism had no impact on M1 markers when compared to cisplatin. However, YM1, an M2 marker and an important molecule for the wound healing process, was decreased in mice treated with kinin B1 receptor antagonist, compared to cisplatin alone. Endothelin-1 levels were also increased in mice with B1 receptor inhibition. This study showed that kinin B1 receptor inhibition exacerbated cisplatin-induced chronic renal dysfunction and fibrosis, associated with reduced YM1 M2 marker expression, thus possibly affecting the wound healing process.

Protective Effect of Adiantum Capillus Against Chemically Induced Oxidative Stress by Cisplatin.

Damage to cells caused by free radicals has been implicated in the disease progression of at least 50 diseases that is cancer, cardiovascular disease, renal dysfunction and other. So many factors contribute to oxidative stress. Hence, the present study was designed to investigate the potential nephroprotective activity of 250mg/kg and 500mg/kg. Ethanolic extract of Adiantum capillus-veneris dried fronds against Cisplatin induced oxidative stress caused in male Wistar rats. Acute nephrotoxicity was induced by i.p. injection of Cisplatin (7 mg/kg of body weight (b.w.)). Administration of ethanol extract at dose level of 500 and 250 mg/kg (b.w.) to Cisplatin-intoxicated rats (toxic control) for 14 days attenuated the biochemical and histological signs of nephrotoxicity of Cisplatin in dose-dependent fashion. Ethanol extract at 500 mg/kg decreased the serum level of creatinine and urea as compared to the toxic control group. The ethanol extract of Adiantum capillus-veneris at 500 mg/kg (b.w.) exhibited significant and comparable nephroprotective potential. The statistically (one-way-ANOVA followed by Dunnet’s test) processed results suggested the positive action of Adiantum capillus-veneris Cisplatin-induced nephropathy.

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

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.

Mechanism of Amelioration of Cisplatin Nephrotoxicity by Procaine Treatment in Mice / 대한마취과학회지

BACKGROUND: Procaine binds to DNA and reduces cisplatin nephrotoxicity, but the mechanism is poorly understood. We explored whether procaine amelioration of cisplatin nephrotoxicity was related to down-and/or up-regulation of inflammatory response gene tumor necrosis factor-alpha (TNF-alpha), oxidative stress indicator gene heme oxygenase-1 (HO-1) or cell cycle inhibitor gene p21. METHODS: Cisplatin and procaine were intraperitoneally injected to mice at a single dosage of 16 and 80 mg/kg, respectively. Renal evaluation was performed 72 hours after cisplatin administration. The expression of transcripts and proteins was analyzed using real time RT-PCR and Western blot, respectively. RESULTS: Procaine treatment moderately attenuated necrotic changes of renal proximal tubules and increases in BUN and creatinine concentration by cisplatin administration. Kidney platinum level between the cisplatin (cis) group and the cisplatin + procaine (CisPro) group was not different. Although the level of TNF-alpha mRNA increased 4-fold higher in the Cis group than in the control, this increase was not attenuated by procaine treatment. Gene expression of p21 and HO-1 was elevated 175 and 4-times higher in the Cis group than in the control, respectively. But their expression was no further elevated, rather significantly reduced in the CisPro group compared to the Cis group. Protein abundance of p21 and HO-1 was paralleled by their respective mRNA expression. CONCLUSIONS: Procaine amelioration of cisplatin nephrotoxicity is likely to be achieved through processes other than the regulation of TNF-alpha, HO-1 or p21 gene expression.

A Case of Minimal Change Disease during Chemotherapy of Bronchogenic Adenocarcinoma / 대한신장학회잡지

A 60 year-old woman was admitted with generalized edema. The patient had bronchogenic adenocarcinoma which was diagnosed 8 months ago, and treated with 3 cycles of etoposide and cisplatin and 6 cycles of paclitaxel and carboplatin. After completion of chemotherapeutic cycles, massive proteinuria (18, 018 mg/day) developed. Renal biopsy revealed minimal change disease, acute tubular necrosis and chronic interstitial nephritis. In spite of continuous chemotherapy, there was no evidence of remission of cancer lesion on a serial consecutive radiographic study. She quitted continuing chemotherapy, and alternative day high dose of prednisolone was initiated for minimal change disease. Proteinuria was decreased dramatically (180 mg/day) after 2 months, and did not recur during tapering of prednisolone. Although bone metastasis on the right femur was newly detected after 2 months, proteinuria did not develop. We experienced minimal change disease during chemotheraphy of bronchogenic adenocarcinoma, thus we report it with article review.

A study of cisplatin nephrotoxicity / 영남의대학술지

To evaluate the nephrotoxicity of cisplatin, serum levels of sodium, potassium, chloride, calcium, phosphorous, magnesium, BUN, creatinine and creatinine clearance were measured before and after administration of cisplatin in 18 cases of patients with malignant neoplasm. The results were as follows: 1) Serum calcium, magnesium, potassium and BUN levels were changed after cisplatin administration, but those changes were not statistically significant. 2) The mean value of creatinine clearance was not decreased significantly after treatment with cisplatin. 3) Acute renal failure was developed in one case, and four cases of hypocalcemia, hypomagnesemia were also detected after administration of cisplatin.