Dapagliflozin Attenuates Renal Tubulointerstitial Fibrosis Associated With Type 1 Diabetes by Regulating STAT1/TGFβ1 Signaling

Abstract

Tubulointerstitial fibrosis (TIF) plays an important role in the progression of renal fibrosis in diabetic nephropathy (DN). Accumulating evidence supports a crucial inhibitory effect of dapagliflozin, a SGLT2 inhibitor, on TIF, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing TIF as well as its possible impact on renal function. TIF in human kidney biopsies obtained from patients with DN was quantified by histopathological staining. In vitro , HK-2 cells were incubated in high glucose with dapagliflozin or fludarabine, and epithelial-mesenchymal transition (EMT) was determined. In vivo experiments were performed in streptozotocin (STZ)-induced type 1 diabetic mice treated with dapagliflozin by gavage for 16 weeks, after which specific functional characteristics and TIF were analyzed. In both DN patients and diabetic mice, fibronectin and Col IV, as well as STAT1 protein in the kidneys were increased as compared with controls. Dapagliflozin significantly decreased blood glucose, and renal STAT1 and TGF-β1 expression in mice. Furthermore, dapagliflozin improved renal function, and attenuated diabetes-induced TIF. In HK-2 cells, dapagliflozin, and fludarabine directly decreased aberrant STAT1 expression and reversed high glucose-induced downregulation of E-cadherin and α-SMA induction. Thus, the results demonstrate that dapagliflozin not only improves hyperglycemia but also slows down the progression of diabetes-associated renal TIF by improving hyperglycemia-induced activation of the STAT1/TGF-β1 pathway.

SGLT2 inhibition by intraperitoneal dapagliflozin mitigates peritoneal fibrosis and ultrafiltration failure in a mouse model of chronic peritoneal exposure to high-glucose dialysate

“…For example, dapagliflozin promoted antifibrotic effects in a type 1 diabetic kidney disease model by ameliorating O-GlcNAcylation and reducing tubular hypoxia,[25] while others have found a downregulation in the Stat1/TGF-β pathway as well as decreased epithelial-to-mesenchymal transition. [26] Importantly, beneficial effects of SGLT2 inhibition were also demonstrated in non-diabetic kidney disease such as hypertensive nephropathy and were attributed to anti-inflammatory effects. [27] Similarly, anti-fibrotic effects of SGLT2 inhibition were found in liver[9] and heart,[10] where administration of dapagliflozin reduced cardiac fibrosis by stimulating M2 macrophages and inhibiting myofibroblast differentiation.…”

“…These changes are in keeping with evidence from other organs where SGLT2 inhibition has been associated with antifibrotic effects, most prominently in the kidney but also in the heart and the liver. For example, dapagliflozin promoted antifibrotic effects in a type 1 diabetic kidney disease model by ameliorating O-GlcNAcylation and reducing tubular hypoxia,[25] while others have found a downregulation in the Stat1/TGF-β pathway as well as decreased epithelial-to-mesenchymal transition [26]. Importantly, beneficial effects of SGLT2 15/23…”

SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate

“…These changes are in keeping with evidence from other organs where SGLT2 inhibition has been associated with antifibrotic effects, most prominently in the kidney but also in the heart and the liver. For example, dapagliflozin promoted antifibrotic effects in a type 1 diabetic kidney disease model by ameliorating O -GlcNAcylation and reducing tubular hypoxia [ 25 ], while others found a downregulation in the Stat1/TGF-β pathway, as well as decreased epithelial-to-mesenchymal transition [ 26 ]. Importantly, beneficial effects of SGLT2 inhibition were also demonstrated in nondiabetic kidney disease such as hypertensive nephropathy and were attributed to anti-inflammatory effects [ 27 ].…”

Asymmetric dimethylarginine (ADMA) accelerates renal cell fibrosis under high glucose condition through NOX4/ROS/ERK signaling pathway

“…Each pathway is regulated by a stimulus and other downstream regulators. Previous studies have suggested that myofibroblast activation acts as a major contributor to the renal fibrosis as they are the major producer of ECM proteins 25,26 .…”