Genetic Deletion and Pharmacological Inhibition of CD36 Ameliorate Vancomycin-Induced AKI

Background: Vancomycin (VAN) is a widely used glycopeptide antibiotic active against Gram-positive cocci including methicillin-resistant Staphylococcus aureus (MRSA). VAN causes a high incidence of acute kidney injury (AKI), associated with a significantly increased mortality. CD36, also known as scavenger receptor class B type II, is expressed on proximal tubular cells and has been implicated in the pathogenesis of both acute and chronic kidney diseases through mechanisms such as lipid accumulation, inflammatory signaling, and ferroptosis. We evaluated the effects of CD36 knockout (CD36KO) and pharmacological CD36 inhibition on VAN-induced AKI. Methods: Male wild-type (WT) and CD36KO mice were administered (VAN 500 mg/kg/day i.p.) for two consecutive days. Glomerular filtration rate (GFR) was assessed using FITC-sinistrin clearance at baseline and 24 hr after the final VAN dose. Kidney injury was assessed histologically using PAS staining and injury scoring. In a separate cohort, WT mice received VAN in combination with Peptide 5A (5A), a CD36 antagonist. To examine the role of CD36 in VAN-induced cytotoxicity at the cellular level, primary proximal tubular cells (PPTCs) were isolated from WT and CD36KO mice. The cells were exposed to VAN, and cell viability was evaluated using the MTT assay. Results: In vivo, VAN treatment led to a significant decline in GFR and increased PAS injury scores. CD36KO mice had significantly attenuated GFR decline compared to WT mice (log fold change in GFR: WT = -2.24 ± 0.746 vs CD36KO = 0.251 ± 0.477, p < 0.001). Similarly, Peptide 5A treatment also mitigated GFR reduction (vehicle = -1.71 ± 0.399 vs 5A = -0.936 ± 0.357, p < 0.01). Both CD36KO and 5A-treated mice also showed significantly lower PAS injury scores than WT controls. In vitro, VAN-treated PPTCs from CD36KO mice had higher viability compared to those from WT mice. Conclusion: In conclusion, both genetic deletion and pharmacological inhibition of CD36 can ameliorate VAN-induced AKI in vivo. CD36 expression on proximal tubular cells contributes to VAN-induced cytotoxicity. Peptide 5A has the protective mechanism will require further study but could include blockade of vancomycin entry into the cell, reduced inflammation, and/or cell death. Funding: NIDDK Support