Up-regulation of matrix metalloproteinases-9 in the kidneys of diabetic rats and the association with neutrophil gelatinase-associated lipocalin

Haiping Chen,Fenghua Liu,Qing Ma,Huayu Yang

doi:10.1186/s12882-021-02396-w

Haiping Chen, Fenghua Liu + Show 2 more

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https://doi.org/10.1186/s12882-021-02396-w

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Abstract

BackgroundMatrix metalloproteinases-9 (MMP-9) can regulate extracellular matrix deposition in diabetic glomerular injury. However, it remains unknown whether MMP-9 is involved in the renal tubular injury. Meanwhile, neutrophil gelatinase-associated lipocalin (NGAL), defined as a biomarker of proximal tubular injury, may influence MMP-9 by forming the MMP-9/NGAL complex. The aim of this study was to investigate MMP-9 expression in proximal renal tubules and the relationship of MMP-9 and NGAL in diabetic rat model treated with Valsartan.MethodsSprague Dawley rats were randomly divided into three groups: Diabetic group, Control group, and Treated group. The diabetic rat model was established by injection of streptozotocin. Related indexes were measured at the end of the 2nd, 4th, 8th and 12th week post-modeling.ResultsIn diabetic groups, the concentrations of MMP-9 markedly increased in the serum and urine of rats in the early stage, even before the appearance of pathological albuminuria. Markedly elevated MMP-9/NGAL complex concentrations were also tested in diabetic groups. Western blot and qPCR tests confirmed that MMP-9 expression levels in the proximal renal tubular epithelial cells of diabetic rats were significantly higher than in control groups (P < 0.05). Correlation analysis showed that MMP-9 was positively correlated with NGAL at both protein and gene expression levels. In addition, Valsartan observably reduced tubular injury as well as MMP-9 expression in diabetic rats.ConclusionsIn diabetic kidney injury, the expression of MMP-9 in the proximal renal tubular epithelial cells was significantly increased. Besides, a positive correlation was found between MMP-9 and NGAL expression, along with high levels of MMP-9/NGAL complex, which indicated that NGAL might participate in the regulation of MMP-9 expression. The administration of Valsartan may reduce this effect.

Highlights

Matrix metalloproteinases-9 (MMP-9) can regulate extracellular matrix deposition in diabetic glomerular injury
We investigated the MMP-9 expression in proximal renal tubules and the relationship of MMP9 and neutrophil gelatinase-associated lipocalin (NGAL) in diabetic models, as well as the effect of Valsartan on the MMP-9 expression
Diabetic rats showed a gradual increase in blood glucose, Serum creatinine (Scr), and blood urea nitrogen (BUN) compared to a non-diabetic control group in the same period

Summary

Introduction

Matrix metalloproteinases-9 (MMP-9) can regulate extracellular matrix deposition in diabetic glomerular injury. It remains unknown whether MMP-9 is involved in the renal tubular injury. The aim of this study was to investigate MMP-9 expression in proximal renal tubules and the relationship of MMP-9 and NGAL in diabetic rat model treated with Valsartan. Our previous study discovered that proximal tubular injury appears before the appearance of pathological proteinuria in the early stage of DN, suggesting that tubular lesions occur earlier than glomerular lesions [1]. Previous studies have confirmed that matrix metalloproteinase-9 (MMP-9) can regulate extracellular matrix (ECM) degradation during renal fibrosis [2, 3]. Contrary, elevated expression of MMP-9 in DM has been shown to directly stimulate the secretion of activated growth factors, such as TNF-α、IL-1β and VEGF, leading to renal injury [7, 8]

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