Renoprotection of dapagliflozin in human renal proximal tubular cells via the inhibition of the high mobility group box 1‑receptor for advanced glycation end products‑nuclear factor‑κB signaling pathway

Abstract

Sodium‑glucose co‑transporter 2 (SGLT2) inhibitors are recently developed oral hypoglycemic agents, which act on renal proximal tubules by reducing the reabsorption of glucose and increasing the excretion of glucose in the urine. However, the mechanism underlying renoprotection has not been fully elucidated. Previous studies have indicated that the expression of high mobility group box 1 (HMGB1) increased in patients with kidney disease, and may result in renal damage through the activation of nuclear factor‑κB (NF‑κB) and an increase in receptor for advanced glycation end products (RAGE) expression. The aim of the present study was to evaluate the effects of the SGLT‑2 inhibitor dapagliflozin on cultured human proximal tubular epithelial cells (HK‑2). HK‑2 cells were grown under high glucose conditions for 48 h in the presence or absence of dapagliflozin. The markers of oxidative stress, inflammation and fibrillation levels were then detected by reverse transcription‑quantitative polymerase chain reaction and western blotting. Hyperglycemia increased the mRNA expression and protein levels of malondialdehyde (MDA), superoxide dismutase (SOD), monocyte chemoattractant protein‑1 (MCP‑1), intercellular adhesion molecule‑1 (ICAM‑1), fibronectin (FN), collagenase type 1 (COL‑1), HMGB1, RAGE and NF‑κB, and the effects could be reversed by dapagliflozin in a concentration‑dependent manner. The results of the present study suggested that HMGB1 increased the expression and secretion of markers of inflammation, oxidative stress and fibrillation, including MDA, SOD, MCP‑1, ICAM‑1, FN and COL‑1, in diabetic nephropathy. However, dapagliflozin significantly reduced the levels of inflammatory markers and postponed the progression of renal injury. It was therefore suggested this may be mediated through the inhibition of HMGB1‑RAGE-NF‑κB signaling pathway.

Prognostic value of arterial stiffness measurements in cardiovascular disease, diabetes, and its complications: The potential role of sodium‐glucose co‐transporter‐2 inhibitors

“…In short, major pathophysiologic mechanisms underlying increased arterial stiffness in diabetes mellitus include the formation of advanced glycation end products (AGEs) on the arterial wall, inducing cross‐linking of collagen molecules and subsequent loss of collagen elasticity, increased activity of renin‐angiotensin‐aldosterone system (RAAS), chronic inflammation, enhanced oxidative stress, and endothelial dysfunction (Figure ) . It has been therefore shown (mainly in experimental models) that SGLT‐2 inhibition decreases the expression of AGEs and their receptor (RAGE), while it also suppresses oxidative stress and inflammatory response . It has been also demonstrated that SGLT‐2 inhibition might provide a significant, beneficial effect on endothelial dysfunction in T2DM, although results are contradictory in shorter duration studies .…”

Acute Kidney Injury Events in Patients With Type 2 Diabetes Using SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs: A Retrospective Cohort Study

“…29,30 In addition to decreasing hypoxic stress, SGLT2 inhibitors may also increase cellular adaptation to hypoxia through cellular signalling, decreased inflammation, and stabilization of kidney tubular and mesangial cells. [31][32][33] Further research is needed to better elucidate the mechanism of renoprotection, as well as ongoing concerns for other adverse events associated with SGLT2 inhibitors.…”

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

“…Several in vitro studies using immortalized human tubular epithelial cells (e.g., HK2 cell line) [25][26][27][28], murine tubular epithelial cells [29] or non-renal cells [30,31] investigated either the effects of empa-or of dapagliflozin. Some of them have shown that SGLT2 inhibition reduced the release of inflammatory or fibrotic factors induced by high glucose levels [25][26][27], others found effects on oxidative stress responses [26,30,31]. Our current study looked at whether high glucose induced changes were influenced by either of the two gliflozins.…”