Abstract
The accumulation of glomerular extracellular matrix (ECM) is one of the critical pathological characteristics of diabetic renal fibrosis. Fibronectin (FN) is an important constituent of ECM. Our previous studies indicate that the activation of the sphingosine kinase 1 (SphK1)-sphingosine 1- phosphate (S1P) signaling pathway plays a key regulatory role in FN production in glomerular mesangial cells (GMCs) under diabetic condition. Among the five S1P receptors, the activation of S1P2 receptor is the most abundant. Berberine (BBR) treatment also effectively inhibits SphK1 activity and S1P production in the kidneys of diabetic models, thus improving renal injury. Based on these data, we further explored whether BBR could prevent FN production in GMCs under diabetic condition via the S1P2 receptor. Here, we showed that BBR significantly down-regulated the expression of S1P2 receptor in diabetic rat kidneys and GMCs exposed to high glucose (HG) and simultaneously inhibited S1P2 receptor-mediated FN overproduction. Further, BBR also obviously suppressed the activation of NF-κB induced by HG, which was accompanied by reduced S1P2 receptor and FN expression. Taken together, our findings suggest that BBR reduces FN expression by acting on the S1P2 receptor in the mesangium under diabetic condition. The role of BBR in S1P2 receptor expression regulation could closely associate with its inhibitory effect on NF-κB activation.
Highlights
Renal fibrosis, including glomerulosclerosis and tubulo-interstitial fibrosis, is one of the major pathological changes caused by progressive diabetic nephropathy (DN)
We have previously reported that high glucose (HG) stimulated glomerular mesangial cells (GMCs) proliferation and extracellular matrix (ECM) component-fibronectin (FN) expression leading to ECM deposition, which initiated and accelerated the pathological progression of DN [5]
The current research further explored the relationship between the protective effects of BBR on DN and S1P2 receptor in the sphingosine kinase 1 (SphK1)/sphingosine 1- phosphate (S1P) signaling pathway
Summary
Renal fibrosis, including glomerulosclerosis and tubulo-interstitial fibrosis, is one of the major pathological changes caused by progressive diabetic nephropathy (DN). It is characterized by glomerular mesangial cells (GMCs) proliferation, excessive accumulation of extracellular matrix (ECM) proteins, mesangial expansion and thickening of the glomerular basement membrane in the early stage, as well as glomerulosclerosis and tubulointerstitial fibrosis in the late stage, which eventually results in the loss of renal function [1,2]. Changes in the quantity and physiological function of GMCs, including phagocytosis, scavenge dysfunction, as well as excessive synthesis and secretion of ECM, play important roles in the pathological development of DN [3,4]. The intervention of ECM synthesis or promotion of its degradation in GMCs with the subsequent prevention and delay of renal fibrosis would be greatly significant in DN treatment [6]
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