Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinases-1 in Acute Pyelonephritis and Renal Scarring

Abstract

The aim of the present study was to elucidate the role of matrix metalloproteinase-9 (MMP-9), and its main inhibitor tissue inhibitor of metalloproteinases-1 (TIMP-1), in acute pyelonephritis and the process of renal scarring. Urine samples from 40 children with acute pyelonephritis, 16 children at 6-wk follow-up and 15 children with nonrenal fever were analyzed using ELISA. MMP-9 and TIMP-1 levels were compared with the outcome of pyelonephritis as measured by renal static scintigraphy. A mouse model of acute ascending pyelonephritis was used to localize the sites of production and the kinetics of MMP-9 and TIMP-1 using immunohistochemistry and ELISA. Human renal epithelial A498 cells, primary mesangial cells and monocytic THP-1 cells were stimulated by Escherichia coli. MMP-9 and TIMP-1 mRNA was analyzed by reverse transcription-PCR (RT-PCR) and protein production by ELISA. We demonstrate a significant increase of MMP-9 and TIMP-1 in the urine of children with acute pyelonephritis. Both proteins were produced mainly by leukocytes, and TIMP-1 also by resident kidney cells. Cells reacted differently after stimulation by bacteria. In mesangial cells and monocytes a decreased constitutive TIMP-1 production was found, which was in contrast to epithelial cells. Out of 40 children with pyelonephritis, 23 had higher urinary TIMP-1 than MMP-9 levels. These children had significantly more severe changes in both acute and follow-up scintigraphy scans indicating higher degree of acute tissue damage and renal scarring. Thus, our findings suggest an association between TIMP-1 and the process of renal scarring. Interstitial fibrosis is the final common end-point of progressive renal diseases. Despite its clinical significance, the mechanisms of scar formation in the kidney are still not fully understood. Generally, it is thought that the renal fibrogenesis is induced by the release of chemokines and growth factors by a number of resident cells. Their concentration gradient results in an influx of leukocytes and an increase in the number of interstitial fibroblasts. The induction phase is followed by an increased matrix production and reduced matrix degradation, which add up to a deposition of extracellular matrix (ECM) components (1). However, ECM component deposition does not seem to be the only mechanism in the pathogenesis of scarring. After direct inoculation of Escherichia coli into the kidneys of rats, contraction and collapse of the tubulointerstitial parenchyma had a greater influence than new collagen production on final fibrosis (2). In line with that, we have previously shown that mouse kidneys after experimental acute pyelonephritis were smaller compared with those from uninfected animals (3). Likewise, it seems that the end-stage kidney is rather shrunken, not enlarged or full of collagen (4).The current hypothesis suggests that the normal remodeling and healing is a result of the balance between ECM protein synthesis and degradation (5). Out of a number of matrixdegrading enzymes, gelatinases, matrix metallopro...

Respective Predictive Role of Urinary Albumin Excretion and Nonalbumin Proteinuria on Graft Loss and Death in Renal Transplant Recipients

“…Our results may thus be important. Other proteins were associated with renal lesions in nontransplanted populations: urinary transferrin excretion (linked to early glomerular change in diabetic patients [6,7]), nephrinuria (associated to glomerular damage in diabetic patients [8]), matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 (associated to renal scarring [9] or urinary cystatine C [10]). Whether these proteins play a role in renal function degradation is presently unknown in renal transplantation.…”

Changes in Matrix Metalloproteinases and Their Inhibitors in Kidney Transplant Recipients

“…32 Throughout the literature, attempts to visulalise MMPs and TIMP by immunohistochemistry both in the kidney and in other tissues, as well as our own attempts, including in situ MMP activity assays, have consistently demonstrated the vast bulk of MMPs and TIMPs in an intracellular cytoplasmic location. 22,[33][34][35][36][37] This conflicts with the perceived primary location ascribed to MMPs and TIMPs, which is based predominantly on in vitro cell culture studies that have positioned the MMP/TIMP system as extracellular owing to its function in ECM degradation and matrix remodeling as well as adhesion. 38,39 Therefore, we would have expected to find both MMPs and TIMPs mainly in the interstitium.…”

Renoprotective mechanisms of pirfenidone in hypertension-induced renal injury: through anti-fibrotic and anti-oxidative stress pathways

“…In particular, PFD inhibits total Smad2/3 protein expression and TGFβ-induced Smad2 phosphorylation in murine mesangial cells (27). The balance between MMPs and TIMPs is also influenced by TGFβ in the kidneys (8,10,25). Furthermore, TGFβ stimulates fibroblast proliferation in the renal interstitium via a Smad-independent signaling pathway (39).…”