Aberrant activation of Notch-1 signaling inhibits podocyte restoration after islet transplantation in a rat model of diabetic nephropathy

Abstract

Signaling abnormalities play important roles during podocyte injury and have been indicated as crucial events for triggering many glomerular diseases. There is emerging evidence demonstrating significant improvements in preventing renal injury and restoring podocytes after islet transplantation. However, whether signaling abnormalities affect the therapeutic efficacy of islet transplantation remain unclear. This study was established to investigate the impact of Notch-1 signaling activation on renal injury and podocyte restoration after islet transplantation. Experiments were performed in vivo and in vitro under conditions of diabetic nephropathy and high-glucose medium, respectively. Podocyte injury in vitro was induced by high-glucose concentration, and expression levels of genes associated with the Notch-1 pathway were also regulated by Jagged-1/FC and N-[N-(3,5-Difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT). Podocytes were co-cultured with islets to investigate the protective effect of islets in high-glucose conditions. Histopathological staining and transmission electron microscopy were performed to assess pathological changes in podocytes in glomeruli. The results from this study showed that Notch-1 signaling in podocytes was significantly decreased by functional islet cells in vivo and in vitro. Compared with the co-cultured group and transplanted group, highly activated Notch-1 signaling significantly moderated the effect of islets in affecting podocyte restoration and renal injury. Renal damage and podocyte injury were alleviated after DAPT treatment. Furthermore, the balance between apoptosis and autophagy was diverse under different treatments. All the data in this study showed that highly activated Notch-1 signaling could affect the therapeutic efficacy of islet transplantation on renal injury and podocyte restoration in high-glucose conditions. The balance between apoptosis and autophagy was also closely associated with the degree of podocyte restoration. This finding may suggest that the in vivo microenvironment plays a critical role in podocyte restoration after islet transplantation, which provides a promising and individual assessment and targeting treatment for different diabetic nephropathy patients after islet transplantation into the future.

Notch inhibitor mitigates renal ischemia‑reperfusion injury in diabetic rats

“…renal damage is alleviated after daPT injection (30). Further evidence has indicated that the jagged1/notch signaling pathway serves a critical role in TGF-β2-induced eMT in human rPe cells (31).…”

Protective Effect of Valsartan on Podocyte Injury in Rats with Diabetic Nephropathy

“…Nephrin-WT1-P-Cadherin complex is a key functional unit that constitutes a ruptured membrane and is an important condition for maintaining glomerular filtration function [10,11]. Studies have shown that P-Cadherin is a structural protein of the podocyte membrane and concentrates on the tight junction between the foot processes, which binds the tight junction protein to the actin of the podocytes and acts as a scaffold [12,13]. WT1 is another important protein that maintains the function and structure of the podocyte membrane.…”

Mechanism of NHX1 Inhibiting TRPV5-Mediated Podocyte Injury in Diabetic Nephropathy

“…Its pathogenesis is closely related to many factors [6]. Podocytes are an important component of the glomerular filtration barrier, and almost all glomerular diseases are associated with podocyte injury [7]. Therefore, elucidating the mechanism of podocyte injury in diabetic nephropathy will help provide a new strategy for the prevention and treatment of DN.…”