Matrix metalloproteinases (MMP-2,9) and their tissue inhibitors (TIMP-1,2) as novel markers of stress response and atherogenesis in children with chronic kidney disease (CKD) on conservative treatment

Abstract

The system of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may play a key role in atherogenesis of chronic kidney disease (CKD) patients by its impact on matrix accumulation. Connections with inflammation, stress, or endothelial dysfunction are also probable. However, the data on correlations between these parameters in CKD patients are scarce in adults and absent in children. The aim of our study was to evaluate serum concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2, as well as their correlations with markers of stress response (Hsp90-α, anti-Hsp60), endothelial dysfunction (sE-selectin), and inflammation (high-sensitivity C-reactive protein) in CKD children treated conservatively. Thirty-seven patients were divided into two groups according to the CKD stage (gr.CKDI, 19 children with CKD stages 2–3; gr.CKDII, 18 subjects with CKD stages 4–5). Twenty-four age-matched healthy subjects served as controls. Serum concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, Hsp90-α, anti-Hsp60, and sE-selectin were assessed by ELISA. Median values of MMP-2, MMP-9, TIMP-1, and TIMP-2 were significantly higher in all CKD children vs. controls and were increased in patients with CKD stages 4–5 vs. CKD stages 2–3. Hsp90-α, anti-Hsp60, sE-selectin, and glomerular filtration rate predicted the values of MMPs and TIMPs. Chronic kidney disease in children is characterized by MMP/TIMP system dysfunction, aggravated by the progression of renal failure. Correlations between examined parameters, heat shock proteins, and markers of endothelial damage suggest the possibility of MMP/TIMP application as indicators of stress response and atherogenesis in children with CKD on conservative treatment.

Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases

“…Reduced MMP proteolytic activity or an increase of tissue inhibitors of MMP (TIMPs) was thought to account for extracellular matrix accumulation and fibrosis [14,19] . Discovery of their in vivo physiological non-extracellular matrix substrates in recent years has revealed diverse biological functions of MMPs.…”

“…Besides the known roles for MMPs in extracellular matrix remodeling, they were found to be critical in recruitment and chemotaxis of inflammatory cells [17] . Elevated serum levels MMP-2 and -9 have been found in CKD patients [18] while increased levels of MMPs may serve as stress markers in these patients [19] . Previous studies have shown that macrophages play a critical role in progression of kidney fibrosis of all forms of chronic kidney diseases [20][21][22] .…”

Urine matrix metalloproteinases and their extracellular inducer EMMPRIN in children with chronic kidney disease

“…13,14 Our preliminary investigation has revealed elevated serum MMPs in children during both pre-dialysis and dialysis periods. 15,16 However, none of those analyses has examined urine concentrations of metalloproteinases or potential correlations between them and corresponding serum values. Our investigation has shown for the first time the significantly increased concentrations of MMP-2 and MMP-9 both in serum and urine of children with the advanced stages of CKD, as well as statistically significant correlations between them.…”

“…The increased serum levels of MMPs have been described both in children and adults with CKD, [13][14][15][16] whereas the EMMPRIN analysis in the CKD population concerned only our previous investigation. 15,16 However, the knowledge about excretion of MMPs with urine, as well as about their potential applicability as the indicators of interstitial fibrosis in that group of patients, is limited to the experimental data and considers renal transplantation.…”

“…15,16 However, the knowledge about excretion of MMPs with urine, as well as about their potential applicability as the indicators of interstitial fibrosis in that group of patients, is limited to the experimental data and considers renal transplantation. 17,18 There are no results of such investigation in the patients with CKD-either children or adults.…”