Abstract
The therapeutic use of numerous pharmacological agents may be limited due to their nephrotoxicity and associated kidney injury. The aim of our study is to test the hypothesis that the blockade of tyrosine kinase-linked receptors signaling protects against chemically induced nephrotoxicity. To test our hypothesis, we investigated sunitinib as an inhibitor for tyrosine kinase signaling for both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR) against adenine-induced nephrotoxicity. Four groups of adult male Swiss albino mice were investigated: normal group, adenine group, sunitinib group, and the adenine+sunitinib group that received concurrent administration for both adenine and sunitinib. Kidney function and oxidative stress biomarkers were analyzed. Tubular injury and histopathological changes were examined. Renal expression of B-cell lymphoma-2 (Bcl-2), the tumor suppressor p53, transforming growth factor beta-1 (TGF-β1), phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phospho-signal transducer and activator of transcription (phospho-STAT3) were measured. The results obtained showed significant improvement (p < 0.05) in kidney function and antioxidant biomarkers in the adenine+sunitinib group. Kidney fibrosis and tubular injury scores were significantly (p < 0.05) less in the adenine+sunitinib group and that of p53 expression as well. Furthermore, sunitinib decreased (p < 0.5) renal levels of TGF-β1, p-ERK1/2, and phospho-STAT3 while elevating Bcl-2 expression score. In conclusion, sunitinib diminished adenine-induced nephrotoxicity through interfering with profibrogenic pathways, activating anti-apoptotic mechanisms, and possessing potential antioxidant capabilities.
Highlights
End-stage renal disease (ESRD) is considered the direct sequelae of an unsuccessful regeneration of the insulted renal tissues
Receiving sunitinib alone had no significant effect on measured biomarkers when compared to the normal group
Concurrent sunitinib administration with adenine decreased creatinine and urea (p < 0.001) levels in serum compared to receiving adenine alone (Figures 1a and 1b, respectively)
Summary
End-stage renal disease (ESRD) is considered the direct sequelae of an unsuccessful regeneration of the insulted renal tissues. The concomitant progression of the renal failure in patients with chronic kidney diseases (CKD) is a function of the accompanying tubule-interstitial fibrosis, glomerular insufficiency, and tubular atrophy [1]. The infiltration of immune cells into the tubulointerstatium; activation of fibroblasts and increased extracellular matrix production and deposition; and massive disappearance of arterioles and capillaries (rarefaction) represents the crucial cellular changes that accompany CKD [2]. The current effective manipulation of the CKD problem is either dialysis or kidney graft. Each of these two solutions has its own problems. Dialysis cannot restore any of the lost kidney functions; kidney graft is mainly not available to the patient population in developing countries in addition to the usual shortage of donors
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