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

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.

Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response

“…We verified the mRNA levels of KIM-1, OPN, MCP-1/CCL2, and fibronectin-1 by real-time PCR and showed that KIM-1 was the most highly upregulated in diseased kidneys. These findings are in agreement with our previous reports showing that KIM-1, MCP-1, and OPN were upregulated in the kidneys of diabetic ZD rats [11,13,23].…”

“…KIM-1 upregulation has been shown to correlate with damage to the proximal tubule in both acute and chronic kidney diseases [18,19,20,21,22]. We have previously reported an induction of KIM-1 in proximal tubules of diabetic ZD rats [11,13,23]. Here, we expanded our study to examine the relationship between KIM-1 expression and lipid accumulation in renal tubules of ZO and ZD kidneys.…”

Gossypin attenuates methotrexate-induced nephrotoxicity: Role of COX II/MMP-9 and fas ligand.

“…In accordance with previous reports, gossypin was reported to decrease oxidative stress markers and exerted a protective action in different models of the liver ( The MMPs, an important family of inflammatory enzymes, are sets of structurally associated proteins that are tangled in the extracellular matrix, inducing remodeling of several physiological and pathological circumstances (Cavdar et al, 2017). MMP-9 is one of the MMPs family locally secreted in response to renal pathological settings and may be involved in the initiation and severity of inflammatory kidney disorders (Chen et al, 2017). Furthermore, it was proved that elevated levels of MMP-9 were linked to tubular epithelial/mesenchyme alteration in vitro (Strutz et al, 2002).…”

Preventive Effect of Garlic Oil and Its Organosulfur Component Diallyl-Disulfide on Cigarette Smoke-Induced Airway Inflammation in Mice

“…According to previous studies, CS acts as a potent inducer for ERK phosphorylation, leading to the production of proinflammatory cytokines as well as MMPs [ 28 ]. In various studies, the activation of ERK signaling has been shown to induce MMP-9 expression, which is abolished in the presence of an ERK inhibitor [ 29 , 30 , 31 ]. In particular, Su et al [ 32 ] reported that DADS caused the suppression of the ERK/Fra-1 pathway, resulting in the downregulation of MMP-9 expression.…”