No Cytotoxic and Inflammatory Effects of Empagliflozin and Dapagliflozin on Primary Renal Proximal Tubular Epithelial Cells under Diabetic Conditions In Vitro

Abstract

Gliflozins are inhibitors of the renal proximal tubular sodium-glucose co-transporter-2 (SGLT-2), that inhibit reabsorption of urinary glucose and they are able to reduce hyperglycemia in patients with type 2 diabetes. A renoprotective function of gliflozins has been proven in diabetic nephropathy, but harmful side effects on the kidney have also been described. In the current project, primary highly purified human renal proximal tubular epithelial cells (PTCs) have been shown to express functional SGLT-2, and were used as an in vitro model to study possible cellular damage induced by two therapeutically used gliflozins: empagliflozin and dapagliflozin. Cell viability, proliferation, and cytotoxicity assays revealed that neither empagliflozin nor dapagliflozin induce effects in PTCs cultured in a hyperglycemic environment, or in co-medication with ramipril or hydro-chloro-thiazide. Oxidative stress was significantly lowered by dapagliflozin but not by empagliflozin. No effect of either inhibitor could be detected on mRNA and protein expression of the pro-inflammatory cytokine interleukin-6 and the renal injury markers KIM-1 and NGAL. In conclusion, empa- and dapagliflozin in therapeutic concentrations were shown to induce no direct cell injury in cultured primary renal PTCs in hyperglycemic conditions.

Uric Acid and Oxidative Stress—Relationship with Cardiovascular, Metabolic, and Renal Impairment

“…Other potential advantages from SGLT2 inhibitors may be reduction of anti-inflammatory, anti-oxidant, and anti-fibrotic markers [ 94 ]. In addition, studies with Ipragliflozin, Dapagliflozin, and Empagliflozin found decreased levels for oxidative stress and macrophages markers (MCP-1, NF-kB, 8-OhdG, L-fatty acid, interleukin-6, monocyte-attractive-protein-1) [ 95 , 96 , 97 ]. Regarding adverse effects, the most commonly observed were genital infections, urinary tract infections, bone fractures, or diabetic ketoacidosis [ 89 , 98 ].…”

Kidney Inflammation, Injury and Regeneration

“…Therefore, the development of novel therapies to improve renal regeneration capacity after AKI, to preserve renal function, and to prevent AKI is urgently needed. In this context, we wanted to offer a forum for the publication of new results on renal inflammation, injury and regeneration, as well as for the review and discussion of existing studies from this interesting research field.This Special Issue covers research articles that investigated the molecular mechanisms of inflammation [1-3] and injury [4,5] during different renal pathologies and renal regeneration [6], diagnostics using new biomarkers [7-9], and the effects of different stimuli like medication or bacterial components on isolated renal cells or in vivo models [10][11][12], all of which were summarized in a very simplified manner. Furthermore, this Special Issue contains important reviews that dealt with the current knowledge of cell death and regeneration [13,14], inflammation [15][16][17][18], and the molecular mechanisms of kidney diseases [19][20][21][22].…”

“…Kidney injury leading to focal segmental glomerulosclerosis was shown by variants in the collagen 4A5 gene, demonstrating that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate the causes of kidney injury [5]. In addition, another study suggested that renal disease in colitis mice might be associated with changes in glomerular collagens and glomerular filtration barrier-related proteins [4].No injury or inflammatory effects of two anti-diabetically used gliflozins on proximal tubular epithelial cells that were cultured in hyperglycemic conditions were found [10]. Stimulations with bacterial lipopolysaccharide were used to investigate acute renal fibrosis in a model of sepsis-induced Int.…”

“…No injury or inflammatory effects of two anti-diabetically used gliflozins on proximal tubular epithelial cells that were cultured in hyperglycemic conditions were found [10]. Stimulations with bacterial lipopolysaccharide were used to investigate acute renal fibrosis in a model of sepsis-induced AKI [11] and the inflammatory cascade of obese kidney fibrosis in a metabolic endotoxemia mouse model [12].…”

Analysis of dapagliflozin-induced expression profile of long noncoding RNAs in proximal tubular epithelial cells of diabetic kidney disease

“…In addition, its hypoglycemic effect is independent of islet function and insulin sensitivity [7]. Several studies have shown that DAPA inhibits the expression of SGLT2 in renal tubules and causes renal vascular remodeling, thereby exerting a protective effect on the kidneys [8].…”