Investigating the role of the ALPK1 signaling pathway in the pathogenesis of diabetic retinopathy

Diabetic retinopathy (DR) is a key eye-related complication linked to diabetes. Chronic inflammation is recognized as the main pathological mechanism leading to retinal damage during the onset and progression of DR. Alpha kinase 1 (ALPK1), a member of a recently discovered serine/threonine protein kinase family, is associated with the onset of multiple inflammatory conditions. Dominant mutations in the ALPK1 gene can result in a rare genetic disorder, known as ROSAH syndrome, which is characterized by ocular inflammatory responses. The role of ALPK1 in DR remains largely unclear and necessitates additional research for a better understanding. Therefore, investigating the function and underlying mechanisms of ALPK1 in DR is highly necessary. In this research, ALPK1 expression and inflammatory cytokines levels were examined in db/db diabetic mice. Additionally, BV2 mouse microglial cells were utilized to establish a hypoxia model that mimicked DR conditions, and the influence of ALPK1 knockdown on these conditions was assessed. The effects of ALPK1 knockdown on retinal damage in db/db diabetic mice were also evaluated. In db/db mice, our findings indicated a decrease in retinal cell numbers and irregular retinal blood vessel formation, along with increased levels of ALPK1 and inflammatory markers TNF-α, IL-1β, IL-6, and IL-18. ALPK1 expression was found to be associated with the TIFA/TRAF6 signaling pathway. Knockdown of ALPK1 was shown to reduce the levels of these inflammatory cytokines, diminish GSDMD-mediated pyroptosis signaling, and mitigate the DR-induced retinal cell damage in BV2 cells. Furthermore, reducing ALPK1 expression in the retinas of db/db diabetic mice was observed to slow down retinal cell degeneration and alleviate microvascular injury within the retina. This research indicated the substantial involvement of ALPK1 in the diabetic retinopathy-linked inflammatory cascade and cell pyroptosis. Targeting the ALPK1 signaling pathway could open avenues for novel therapeutic strategies to manage DR.