article · Biomedicine & Pharmacotherapy
Acute kidney injury caused by the chemotherapy drug cisplatin remains difficult to manage due to limited understanding of its underlying mechanisms. This investigation examined the protective effects of rosuvastatin and the flavonoid diosmetin in a rat model of cisplatin-induced kidney damage. Both compounds, tested alone and in combination, reversed renal damage by restoring body weight, blood pressure, and kidney tissue structure. They reduced markers of kidney dysfunction, including serum urea, creatinine, and cystatin c, while lowering inflammation and oxidative stress markers. The treatments switched kidney macrophages from a pro-inflammatory to an anti-inflammatory state and inhibited key inflammatory signalling pathways involving TLR4 and NLRP3. Furthermore, diosmetin demonstrated antibacterial activity against uropathogenic bacteria by disrupting bacterial cell membrane integrity.
Cisplatin is an effective chemotherapy drug, but its tendency to cause severe kidney damage restricts its medical use. Identifying therapeutic agents such as rosuvastatin and diosmetin that protect kidney tissues from cisplatin toxicity while also combating urinary tract bacteria could lead to safer cancer treatments and better management of acute kidney injury.
This research could support the development of adjunctive pharmaceutical therapies to protect patients undergoing cisplatin-based chemotherapy from acute kidney injury. The prospective users would be pharmaceutical developers and clinical oncology teams. As the findings are based on animal models and in vitro antibacterial testing, the work represents early-stage preclinical research that requires extensive further testing before real-world clinical use.
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Numerous efforts to manage acute kidney injury (AKI) were unsuccessful because its pathophysiology is still poorly understood. Thus, our research hotspot was to explore the possible renoprotective effects of rosuvastatin (Ros) and diosmetin (D) on macrophage polarization and the role of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signaling in cis-induced AKI and study the activity of D against uropathogenic bacteria. Fifty-four albino male rats were randomized into 9 groups equally: Control, Ros, D20, D40, untreated Cis, and Cis groups cotreated with Ros, D20, D40 and Ros+D40 for 10 days. Our results indicated that Ros and D, in a dose-dependent manner, markedly restored body weight, systolic blood pressure, and renal histological architecture besides significantly upregulated SOD levels, expression of anti-inflammatory CD163 macrophages, arginase1levels, IL-10 levels,STAT3 and PCNA immunoreactivity. Also, they significantly downregulated renal index, serum urea, serum creatinine, serum cystatin c, inflammatory biomarkers (C reactive protein, IL1β & TNF-α), MDA levels, HSP70/TLR4/MyD88/NF-κB p65/NLRP3 expressions, proinflammatory CD68 macrophages and caspase-3 immunoreactivity, resulting in a reversal of cis-induced renal damage. These findings were further confirmed by molecular docking that showed the binding affinity of Ros and D towards TLR4 and NLRP3. Furthermore, D had antibacterial action with a minimum inhibitory concentration ranging from 128 to 256 µg/mL and caused a delay in the growth of the tested isolates, and negatively affected the membrane integrity. In conclusion, Ros and D had antioxidant, anti-inflammatory and antiapoptotic properties and switched macrophage from proinflammatory CD68 to anti-inflammatory CD163. Additionally, the targeting of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signals are effective therapeutic strategy in AKI.
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DOI: 10.1016/j.biopha.2024.116151
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