TRPM7 Channel-Mediated Mitochondrial Oxidative Stress Induces Dysfunction of Müller Cells Under High Glucose and Low...

Clinical epidemiological data have shown that hypomagnesemia, defined as a serum Mg²⁺ concentration of <0.7 mmol/L, independently increases the risk of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). The molecular and cellular mechanisms through which hypomagnesemia accelerates the onset and progression of DR remain largely undefined. The Transient Receptor Potential Cation Channel, Subfamily M, Member 7 (TRPM7) channel is expressed in the retina and is integral to the pathophysiological processes associated with hypomagnesemia. However, whether TRPM7 affects DR progression through its regulation of hypomagnesemia has not been established. Müller cells span the retina and are crucial for maintaining retinal homeostasis. Moreover, these cells significantly influence the onset and progression of DR. The current study assessed the impact of combined treatment with high-glucose (HG) and low-Mg²⁺ (LM) on retinal Müller cells, and also investigated the underlying molecular mechanism.

Müller cells were treated with HG or HG combined with LM (HG/LM). TRPM7-silenced Müller cells were generated by transduction with shRNA. Quantitative real-time PCR and Western blot analysis were performed to measure the levels of related genes and proteins, respectively. Cell viability, apoptosis, mitochondrial function, oxidative stress, and intracellular Ca²⁺ levels in Müller cells were analyzed using relevant assays.

Low Mg²⁺ was found to aggravate oxidative stress and mitochondrial dysfunction in Müller cells under HG stress, leading to decreased cell viability, increased apoptosis, and elevated expression of vascular endothelial growth factor. These effects were accompanied by the upregulation of TRPM7 and mitochondrial voltage-dependent anion channel 1 (VDAC1), as well as increased intracellular Ca²⁺ levels. Silencing of TRPM7 expression in Müller cells significantly decreased intracellular Ca²⁺, oxidative stress, mitochondrial dysfunction, and cell dysfunction under HG/LM stress.

Low Mg²⁺ exacerbates the dysfunction of Müller cells under HG stress via TRPM7/Ca²⁺/VDAC1 axis-mediated mitochondrial oxidative stress.