Gliflozins Have an Anti-Inflammatory Effect on Renal Proximal Tubular Epithelial Cells in a Diabetic and Inflammatory Microenvironment In Vitro

Abstract

Inflammation is intimately involved in the pathogenesis of diabetic kidney disease. Inhibition of SGLT-2 by a specific class of drugs, gliflozins, has been shown to reduce inflammation and attenuate the progression of diabetic nephropathy, in addition to its main effect of inhibiting renal glucose reabsorption. We used highly purified human renal proximal tubular epithelial cells (PTCs) as an in vitro model to study the cellular response to a diabetic (high glucose) and inflammatory (cytokines) microenvironment and the effect of gliflozins. In this context, we investigated the influence of SGLT-2 inhibition by empa- and dapagliflozin (500 nM) on the expression of pro-inflammatory factors (IL-1β, IL-6, TNF-α, MCP-1, and ICAM-1). The results clearly indicate an anti-inflammatory effect of both gliflozins. Although induced expression of the four cytokines was only slightly attenuated, there was a clear effect on the expression of the adhesion molecule ICAM-1, a master regulator of cellular responses in inflammation and injury resolution. The induced expression of ICAM-1 mRNA was significantly reduced by approximately 13.5% by empagliflozin and also showed an inhibitory trend with dapagliflozin. However, induced ICAM-1 protein expression was significantly inhibited from 24.71 ± 1.0 ng/mL to 18.81 ± 3.9 (empagliflozin) and 19.62 ± 2.1 ng/mL (dapagliflozin). In conclusion, an additional anti-inflammatory effect of empa- and dapagliflozin in therapeutically observed concentrations was demonstrated in primary human PTCs in vitro.

Unveiling the crucial role of intercellular adhesion molecule‐1 in secondary diabetic complications

“…Notably, the ICAM-1 gene has emerged as a potential susceptibility marker for diabetes and DN due to its elevated expression under diabetic conditions, which can be reduced by certain antidiabetic medications like gliflozin. 15,16 These findings suggest that the ICAM-1 gene may be a candidate for susceptibility to T1DM, T2DM, and DN. However, it is important to note that only a small percentage of people with T1DM or T2DM acquire DN, implying a complicated interaction between genetic predisposition and environmental variables.…”

“…The pathogenesis of DN involves complex interactions between metabolic abnormalities, oxidative stress, inflammation, and endothelial dysfunction. Notably, the ICAM‐1 gene has emerged as a potential susceptibility marker for diabetes and DN due to its elevated expression under diabetic conditions, which can be reduced by certain antidiabetic medications like gliflozin 15,16 . These findings suggest that the ICAM‐1 gene may be a candidate for susceptibility to T1DM, T2DM, and DN.…”

The effect of dapagliflozin ointment on induced psoriasis in an experimental model

“…Koch et al . [ 7 ] emphasized the importance of dapagliflozin as an antioxidant and anti-inflammatory drug. The potential for dapagliflozin to modulate cytokine inflammatory pathways in psoriasis remains an area of exploration.…”

Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells

“…Through paracrine signaling, TNF-α induces interleukin (IL)-8 and E-selectin expression in different types of cells and enhances the expression levels and secretion of IL-1β by macrophages. In vitro, however, recombinant TNF-α and interleukin (IL)-1 proteins are usually combined (TNF-α/IL-1β) to induce a general inflammatory response in primary renal cells [5][6][7][8][9].…”