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.
Highlights
Over 90% of the filtered glucose in the kidney is reabsorbed by the sodium-glucose co-transporter 2 (SGLT-2) expressed in the apical brush border membrane of tubular epithelial cells [1,2]
Immunofluorescence staining clearly showed the expression of SGLT-2 in the apical membrane of cells of the proximal tubule in situ (Figure 1A) and PTCS in vitro (Figure 1C)
The staining of human renal sections showed that SGLT-2 is exclusively expressed in the apical brush border membrane of tubular epithelial cells
Summary
Over 90% of the filtered glucose in the kidney is reabsorbed by the sodium-glucose co-transporter 2 (SGLT-2) expressed in the apical brush border membrane of tubular epithelial cells [1,2]. Inhibition of SGLT-2 blocks the reabsorption of glomerularly filtered glucose (and sodium) in the ensuing proximal S1/S2 segment, a mechanism that has been exploited to reduce hyperglycemia in patients with type 2 diabetes mellitus [1]. Based on the selective inhibition of SGLT-2, gliflozins increase urinary glucose excretion by reducing the reabsorption into the bloodstream. In the last few years, the renoprotective function of gliflozins has been described in diabetic nephropathy, which affects approximately 40% of patients with diabetes and is a leading cause of chronic kidney disease worldwide. SGLT2 inhibition has been described as reducing inflammation and attenuating the progression of diabetic nephropathy [4]
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