Celecoxib and naproxen disrupt autophagy and activate EGR1 in kidney tubules

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic effects, although the possible COX-independent impact on the kidneys is largely unknown. Kidney damage is often associated with defective autophagy and autophagy dysregulation has been associated with kidney fibrosis and the pro-fibrotic EGR1 transcription factor activation. The non-selective COX inhibitor indomethacin (IND) can be nephrotoxic, but the impact of selective COX-2 inhibitor celecoxib (CEL) or the non-selective naproxen (NAP) on renal autophagy and EGR1 remain obscure. Here, we investigated the dose-dependent effect of CEL and NAP administration on human proximal tubule epithelial (HK-2) cells and murine inner medullary collecting duct (IMCD) cells in comparison to the effects of IND. To elucidate chronic renal effects, we also treated rats similarly for two weeks. We found that high doses of CEL and NAP, but not IND, disrupted autophagy, increased oxidative stress, and activated pro-fibrotic pathways in both HK-2 and IMCD cells with induced EGR1, accompanied by ACTA2 upregulation. We found similar effects in the renal medulla of rats treated with high-dose CEL and NAP. In addition, autophagy dysfunction was evident through increased LC3-II/I and p62 accumulation. Histology confirmed dose-dependent tubular damage and nuclear EGR1 accumulation in CEL and NAP treated rats, accompanied by induced HMOX1 and AKT phosphorylation. Our study reveals dose-dependent tubulotoxic effects of NSAIDs unrelated to their COX-selectivity, suggesting an interplay between pro-fibrotic transcription factor EGR1, autophagy pathways and oxidative stress. These findings underscore the need for meticulous dose optimization especially in kidney disease patients in order to reduce nephrotoxicity.

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