Small-Dose Sunitinib Modulates p53, Bcl-2, STAT3, and ERK1/2 Pathways and Protects against Adenine-Induced Nephrotoxicity

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.

Impact of Gum acacia on oxidative stress and apoptosis in Adenine-induced CKD animal model

“…Both developed and undeveloped nations, chronic kidney disease are regarded as an aggravating issue. The present guidelines are quite complex because the current approach to treating CKD focuses more on limiting its effects than on curing the illness itself [15]. The findings of the present study demonstrated that Gum acacia treatment improved the measured kidney function parameters, according to biochemical findings and hematological results.…”

“…Here, GA raised kidney Bcl-2 levels while lowering caspase-3 levels. Numerous studies indicated that caspase dependent apoptosis played a significant role in the emergence of tubular damage and renal failure [26] [15]. Therefore, GA has the capacity to control apoptotic pathways, stop renal tissue injury, and then stop the evolution of fibrosis.…”

Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity

“…We also examined both caspase-3 expression and cleaved caspase-3 expression by western blot, as shown in Supplementary Figure S1 , with the increase of apoptosis cells, the expression of cleaved caspase-3 increased in total lysates of original orthotopic tumors. Finally, it was worth noting that studies have revealed the targets of sunitinib are mainly members of the VEGFR family and PDGFR family, which play a vital role in tumor progression ( Saleh et al, 2020 ). An interesting result was obtained by analyzing gene expression data in TCGA databases.…”

Role of endogenous adenine in kidney failure and mortality with diabetes

“…Adenine is known to cause kidney pathology as an exogenous toxin in mouse (25) and rat models ( 14) of CKD, and possibly as an endogenous toxin in humans (26). The pathology of adenine-induced kidney disease includes glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammatory cell infiltration (27,28). The mechanism of adenine induced kidney disease has not been established although it has been postulated that conversion of adenine to 2-8 dihydroxyadenine ( 26) is a driver of CKD in patients with mutations of adenine phosphoribosyltransferase (APRT), the major enzyme that metabolizes adenine to AMP.…”