The assessment of GDF15 as an early indicator for proximal tubular cell injury in acute kidney injury

Acute Kidney Injury (AKI) is a significant medical burden, with current diagnostics detecting it only after full manifestation. Rapid, specific markers for early, subclinical detection are needed. The stress marker, growth differentiation factor 15 (GDF15), has been associated wit kidney injury in critically ill patients. Therefore, GDF15 changes were evaluated across various AKI scenarios to assess its potential as an early marker and explore its induction mechanisms. Serum parameters and renal tissue were analysed in two mouse models: unilateral ischaemia-reperfusion injury (unilateral IRI) and unilateral ureteral obstruction (UUO). GDF15 induction was determined in the human HK-2 proximal tubular cell line under inducer-mediated oxidative stress (tert-butyl hydroperoxide (t-BHP)), hypoxic (CoCl2 ), and inflammatory (tumour necrosis factor (TNF)-α) conditions. In both animal models, serum GDF15 levels peaked within hours of injury and then declined. Renal GDF15 transiently elevated, mainly in aquaporin 1-positive (AQP1+) proximal tubules. In HK-2 cells, Gdf15 mRNA and protein were strongly induced by t-BHP and CoCl2 , and weakly by TNF-α. Antioxidant or MAPK inhibitors blocked t-BHP- and CoCl2 -induced GDF15 expression. HK-2 cells with silenced Nrf2 also had lower basal GDF15 levels. Results of the study showed that raised serum GDF15 levels could be detected in unilateral AKI models early before alterations in renal function parameters. GDF15 expression was also associated with proximal tubular cell injury mediated by oxidative stress and hypoxia. These outcomes suggest that elevated serum GDF15 could be an early biomarker for proximal tubular cell injury in AKI.