Aldosterone, Methylglyoxal, and Glycated Albumin Interaction with Macrophage Cells Affects Their Viability, Activation, and Differentiation.

Background: The inflammatory response in diabetes is strongly correlated with increasing amounts of advanced glycation end products (AGEs), methylglyoxal (MGO), aldosterone (Aldo), and activation of macrophages. Aldo is known to be associated with increased pro-inflammatory responses in general, but its significance in inflammatory responses under glycated circumstances has yet to be understood. In the current work, the aim of our study was to study the macrophage immune response in the presence of AGEs, MGO, and Aldo to comprehend their combined impact on diabetes-associated complications.

Methods And Results: The viability of macrophages upon treatment with glycated HSA (Gly-HSA) promoted cell growth as the concentration increased from 100 to 500 μg/mL, whereas MGO at a high concentration (≥300 μM) significantly hampered cell growth. At lower concentrations (0.5-5 nM), Aldo strongly promoted cell growth, whereas at higher concentrations (50 nM), it was seen to inhibit growth when used for cell treatment for 24 h. Aldo had no effect on MGO-induced cell growth inhibition after 24 h of treatment. However, compared to MGO or Aldo treatment alone, an additional decrease in viability could be seen after 48 h of treatment with a combination of MGO and Aldo. Treatment with Aldo and MGO induced expression of TNF-α independently and when combined. However, when combined, Aldo and MGO significantly suppressed the expression of TGF-β. Aldo, Gly-HSA, and MGO strongly induced the transcription of NF-κB and RAGE mRNA and, as expected, also promoted the formation of reactive oxygen species. Also, by inducing iNOS and MHC-II and suppressing CD206 transcript expression, Gly-HSA strongly favored the differentiation of macrophages into M1 type (pro-inflammatory). On the other hand, the combination of Aldo and MGO strongly induced the expression of MHC-II, CD206, and ARG1 (M2 macrophage marker). These findings suggest that Gly-HSA, MGO, and Aldo differently influence macrophage survival, activation, and differentiation.

Conclusions: Overall, this study gives an insight into the effects of glycated protein and MGO in the presence of Aldo on macrophage survival, activation, differentiation, and inflammatory response.