Selected Metal Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases as Potential Biomarkers for Tubulointerstitial Fibrosis in Children with Unilateral Hydronephrosis

Abstract

Renal tubulointerstitial fibrosis caused by congenital ureteropelvic junction obstruction (UPJO) may lead to the development of obstructive nephropathy (ON) and the impairment of kidney function. Hence, the identification of early biomarkers of this condition might be of assistance in therapeutic decisions. This study evaluates serum and urinary metalloproteinases MMP-1, MMP-2, and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 as potential biomarkers of ON in children with congenital unilateral hydronephrosis (HN) caused by UPJO. Forty-five (45) children with congenital HN of different grades of severity and twenty-one (21) healthy controls were enrolled in the study. Urinary and serum concentrations of MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured using specific ELISA kits. The urinary excretions were expressed as biomarker/creatinine (Cr) ratios. To evaluate the extracellular matrix remodelling process activity, the serum and urinary MMP-1, -2, -9/TIMP-1, -2 ratios were also calculated. In comparison with the controls, patients with HN, independent of the grade, showed significantly increased median serum MMP-9, TIMP-1, and TIMP-2, median urinary MMP-9/Cr, and TIMP-2/Cr ratios. Lower median values of serum MMP-2/TIMP-1, MMP-9/TIMP-1 in patients with HN were also revealed. Additionally, higher urinary MMP-2/Cr, lower urinary MMP-2/TIMP-2, and lower serum MMP-9/TIMP-2 ratios were observed in patients with HN grades 3 and 4. Patients with ON diagnosed by renal scintigraphy had a significantly higher median serum MMP-9 concentration and lower median serum MMP-9/TIMP-1, -2 ratios in comparison with those without this condition. Patients with nonglomerular proteinuria had a significantly higher median serum TIMP-1 concentration, a higher median urinary TIMP-2/Cr ratio, and a lower serum MMP-9/TIMP-1 ratio compared to those without this symptom. The relationship between the measured biomarkers and the relative function of the obstructed kidney showed no correlations. The ROC curve analysis showed a promising diagnostic profile for the detection of ON for serum MMP-9 and the serum MMP-9/TIMP-1 and MMP-9/TIMP-2 ratios. In conclusion, the results of this study suggest that patients with HN, particularly with grades 3 and 4, are at higher risk of renal tubulointerstitial fibrosis. The noninvasive markers of this condition considered are urinary MMP-2/Cr and MMP-9/Cr, serum MMP-9, serum and urinary MMP-2, MMP-9/TIMP-1, -2. Additionally, serum MMP-9 and MMP-9/TIMP-1, -2 may become promising markers of ON.

Effects of secretome derived from macrophages exposed to calcium oxalate crystals on renal fibroblast activation

“…These MMPs play primary role in second step of collagen degradation to break down collagen molecules that have been denatured or cleaved by collagenases 80 . In renal fibrosis, there is increasing evidence demonstrating the roles for MMP-9 and MMP-2 in degradation of denatured collagens, fibronectin, laminin, elastin, and vitronectin 81 , 82 . They are also involved in the ECM remodeling 83 , 84 .…”

Installation of the developing nephron in the fetal human kidney during advanced pregnancy

“…Surprisingly, restricted to the deep lateral aspect, solely here the link between the tuft of the defoliating glomerulus and the ascending perforating radiate artery is observed. Unknown is whether the asymmetrical medial and lateral aspects of the shaping nephron are covered by a different composition of extracellular matrix [ 48 ], whether the site-specific installation is controlled by different matrix metalloproteinases [ 49 ] and whether the before described noxae impairing nephrogenesis can eventually cause at this site an imbalance of these regulating enzymes.…”

“…When the focus is directed to the numerous enzymes and complex molecular interactions, which build up and degrade the extracellular matrix in the interstitium, it is most probable that the noxae impairing nephrogenesis first target at this balance before they affect the developing nephron as it was shown in the fetuses of diabetic rats [ 49 , 50 ]. Since data for preterm and low birth weight babies is lacking, the task for the future is to elaborate, whether for example the expression of matrix metalloproteinases (MMPs) and related tissue inhibitors (TIMPs) are very first influenced by noxae.…”

Promising renoprotective effect of gold nanoparticles and dapagliflozin in diabetic nephropathy via targeting miR‐192 and miR‐21

“…In addition, MMP-2 can enhance the accumulation and production of ECM. [66] Another research [67] reported a positive association between MMP-2 and TGF-β1 urinary excretions, confirming their profibrotic action. Apoptosis and autophagy significantly contribute to developing cellular homeostasis.…”