Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway

Abstract

Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy- induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292].

Fig. 1.. Effect of NPY treatment on cisplatin-induced renal injury. (A) Experimental design to determine the effect of NPY on cisplatin-induced renal injury. (B) Expression of NPY in the kidney of PBS- or cisplatin- treated mice (n = 5). (C) BUN level, (D) Creatinine level. Blood samples were collected on day 3 after cisplatin treatment (n = 5). scale bar: 20 μm. (E) Renal tissues were collected and processed for H&E staining to evaluate tubular damage and histology. *P ＜ 0.05. All error bars indicate S.E.M. All expression levels were normalized against GAPDH mRNA expression.

Fig. 2.. Down-regulation of genes in the p53-dependent apoptosis pathway after NPY treatment. (A) Representative immunofluorescence images of kidneys showing apoptosis (TUNEL-positive nuclei, scale bar: 70 μm). (B) Quantitative real-time PCR analysis showing the expression levels of pro- or anti-apoptotic genes in the renal tissues of each group (n = 5). (C) Western blot analysis and quantification of p53, Bax, and Bcl2 in the renal tissues of each group (n = 6). *P ＜ 0.05. All error bars indicating S.E.M. All expression levels were normalized against GAPDH mRNA expression.

Fig. 3.. NPY ameliorates cisplatin-induced renal injury through Y1 receptor signaling. (A) Expression levels of Y receptors in the kidney (n = 5), (B) BUN level, (C) Serum creatinine level (n = 5), (D) Kidney sections were stained with H&E (n = 5). scale bar: 20 μm; (E) Apoptosis in kidney tissues was examined by TUNEL assay. Representative images of TUNEL staining are shown (original magnification- 400X; scale bar, 70 μm). Quantification of TUNEL-positive cells in the tissues from each condition (n = 5). (F) Quantitative real-time PCR analysis for pro- or anti-apoptotic gene expression in the renal tissues of each group (n = 5). (G) Western blot analysis and quantification of p53, Bax, and Bcl2 levels in the renal tissues of each group (n = 6). *P ＜ 0.05. All error bars indicating S.E.M. All expression levels were normalized against GAPDH mRNA expression.