LATS1 inhibitor and zinc supplement synergistically ameliorates contrast-induced acute kidney injury: Induction of Metallothionein-1 and suppression of tubular ferroptosis
Contrast-induced acute kidney injury (CI-AKI) is a common cause of renal dysfunction in hospitalized patients, yet its precise mechanisms and effective treatments remain unclear. This study explored the role of tubular ferroptosis in experimental CI-AKI models and in primary tubular epithelial cells (PTECs) treated with ioversol. Through whole exome sequencing, we identified metallothioneins (MTs) as some of the most significantly downregulated genes after ioversol exposure. Our findings demonstrate that overexpression of Mt1 reduces, while suppression of Mt1 increases, ioversol-induced tubular ferroptosis. Notably, the level of MTF1 (metal regulatory transcription factor 1), a key regulator of Mt1, rose in response to ioversol treatment. We discovered that ioversol activates LATS1 (Large tumor suppressor homolog 1), a kinase that facilitates the phosphorylation and nuclear translocation of MTF1, thereby inhibiting its transcriptional activity for Mt1. Both genetic and pharmacological inhibition of LATS1 reversed the ioversol-induced suppression of Mt1.
Therapeutically, we administered a combination of the LATS1 inhibitor TDI-011536 and zinc acetate to a rodent model of CI-AKI. Our results show that this combination synergistically upregulates Mt1 expression and protects against contrast media-induced tubular ferroptosis. In summary, our study indicates that reduced Mt1 contributes to tubular ferroptosis associated with CI-AKI. We show that contrast media activate LATS1, which suppresses the transcriptional activity of MTF1 for Mt1. Thus, the combination of zinc acetate and a LATS1 inhibitor presents a promising therapeutic approach for treating CI-AKI.