A novel mechanism of action for salidroside to alleviate diabetic albuminuria: effects on albumin transcytosis across glomerular endothelial cells

Abstract

Salidroside (SAL) is a phenylethanoid glycoside isolated from the medicinal plant Rhodiola rosea. R. rosea has been reported to have beneficial effects on diabetic nephropathy (DN) and high-glucose (HG)-induced mesangial cell proliferation. Given the importance of caveolin-1 (Cav-1) in transcytosis of albumin across the endothelial barrier, the present study was designed to elucidate whether SAL could inhibit Cav-1 phosphorylation and reduce the albumin transcytosis across glomerular endothelial cells (GECs) to alleviate diabetic albuminuria as well as to explore its upstream signaling pathway. To assess the therapeutic potential of SAL and the mechanisms involved in DN albuminuria, we orally administered SAL to db/db mice, and the effect of SAL on the albuminuria was measured. The albumin transcytosis across GECs was explored in a newly established in vitro cellular model. The ratio of albumin to creatinine was significantly reduced upon SAL treatment in db/db mice. SAL decreased the albumin transcytosis across GECs in both normoglycemic and hyperglycemic conditions. SAL reversed the HG-induced downregulation of AMP-activated protein kinase and upregulation of Src kinase and blocked the upregulation Cav-1 phosphorylation. Meanwhile, SAL decreased mitochondrial superoxide anion production and moderately depolarized mitochondrial membrane potential. We conclude that SAL exerts its proteinuria-alleviating effects by downregulation of Cav-1 phosphorylation and inhibition of albumin transcytosis across GECs. These studies provide the first evidence of interference with albumin transcytosis across GECs as a novel approach to the treatment of diabetic albuminuria.

A New Pathogenesis of Albuminuria: Role of Transcytosis

“…Since albumin is negatively charged, it can be restricted by GECs. A previous study demonstrated that albumin trafficked across the endothelial barrier through a caveolae-mediated transcytosis pathway [34]. Recent evidence indicates that glomerular charge and size selectivity is not impaired during the early phase of diabetic nephropathy [40][41][42], and albumin transendothelia transport may be responsible for the formation of albuminuria at the early stage of diabetic nephropathy.…”

“…Under special pathological conditions or genetic defects, the integrity of the GFB is damaged, and then leads to increased permeability to macromolecules and resultant albuminuria. However, recent data has revealed that transcellular transport of plasma albumin across GECs and podocytes may constitute a new glomerular albumin filtration pathway [34][35][36]. Furthermore, insufficient transcytosis by dysfunctional PTCs also contributes to albuminuria.…”

“…Furthermore, insufficient transcytosis by dysfunctional PTCs also contributes to albuminuria. Under physiological conditions PTCs can reabsorb, transcytose Receptor-mediated albumin transcytosis in GECs has been proven to be involved in the formation of albuminuria [34] Podocytes Podocytes have the ability of albumin endocytosis and transcytosis [35,36,44,45,47,50,51,53] PTCs Defects of rat PTCs in endocytosis and transcytosis are involved in the pathogenesis of albuminuria [37,46,57] and process filtered albumin. Albumin is internalized to PTCs via megalin-cubilin-mediated, clathrin-dependent endocytosis.…”

“…Receptor-mediated albumin transcytosis in GECs has been reported to be involved in the formation of albuminuria in a murine model of early stage diabetic nephropathy [34]. However, the precise mechanism by which pathological transcytosis in GECs underlies albuminuria remains unknown.…”

“…Cav-1 is a 20-22 kDa integral membrane protein enriched in caveolae [74,76,77]. In the kidney, Cav-1 is distinctly expressed on the renal cortex of mice and humans [34]. Cav-1 has been found to be significantly increased in the glomeruli of patients with primary and secondary glomerular diseases, such as IgA nephropathy, membranous nephropathy, crescent glomerulonephritis, minimal change disease and diabetic nephropathy [78].…”