Endocytosis of Albumin Induces Matrix Metalloproteinase-9 by Activating the ERK Signaling Pathway in Renal Tubule Epithelial Cells.

Xiaoming Chen,Jasmine George,Xueying Zhao,Fidele Tuyishime,Ashmeer Chima,Alyssa Cobbs

doi:10.3390/ijms18081758

Xiaoming Chen, Jasmine George + Show 4 more

Open Access

https://doi.org/10.3390/ijms18081758

Copy DOI

Abstract

Matrix metalloproteinase-9 (MMP-9) is dysregulated in chronic kidney diseases including diabetic nephropathy. This study was performed to examine the expression of MMP-9 in renal tubule epithelial cells (TECs) under diabetic conditions and its regulatory mechanisms. We characterized MMP-9 protein in diabetic animals and primary cultured rat TECs exposed to exogenous albumin and high glucose. We also used specific inhibitors to determine if internalization of albumin and/or extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were required for MMP-9 secretion. Immunostaining of kidney sections revealed enhanced MMP-9 signal in the damaged proximal tubules in Zucker diabetic fatty (ZDF) rats. ZDF rats also exhibited an albuminuria-related and age-dependent increase in MMP-9 excretion, which was prevented by rosiglitazone. In primary cultured rat TECs, high glucose exposure did not increase MMP-9 secretion. In contrast, administration of rat serum albumin (RSA, 0.1–0.5 mg/mL) resulted in a dose-dependent increase in MMP-9 expression and secretion by TECs, which was abolished in the presence of an ERK1/2-specific inhibitor, U0126. Simvastatin, an inhibitor of albumin endocytosis, also prevented MMP-9 secretion. Taken together, these results demonstrate that endocytosis of albumin stimulates MMP-9 secretion by TECs through the ERK signaling pathway.

Highlights

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and accounts for over one-third of all patients who are on dialysis
DN is characterized by early albuminuria, which often progresses to proteinuria and leads to a decline in excretory renal function associated with glomerulosclerosis and tubulointerstitial fibrosis [1,2]
Albumin has been shown in proximal tubule epithelial cells (TECs) to induce the production of a variety of proinflammatory and profibrotic cytokines such as regulated on activation, normal T cell expressed and secreted (RANTES) [3], monocyte chemoattractant protein-1 (MCP-1) [4,5], and transforming growth factor-β (TGF-β) [6,7], which involves both endocytosis-dependent and -independent mechanisms

Summary

Introduction

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and accounts for over one-third of all patients who are on dialysis. DN is characterized by early albuminuria, which often progresses to proteinuria and leads to a decline in excretory renal function associated with glomerulosclerosis and tubulointerstitial fibrosis [1,2]. Recent studies have shown that MMPs, especially gelatinases (MMP-2 and MMP-9), are involved in the initiation and progression of kidney fibrosis [8]. An increase in MMP-2 and MMP-9 is associated with the induction of tubular cell epithelial–mesenchymal transition (EMT) in vitro [9] and in vivo [10]. Others, have previously demonstrated an increase in urinary MMP-9 excretion in animal models of diabetic kidney disease and proteinuric human disease [11,12,13,14,15,16,17].

Methods

Discussion

Conclusion