Upregulation of tissue inhibitor of metalloproteases-1 (TIMP-1) and procollagen-N-peptidase in hypertension-induced renal damage

Abstract

Background. Hypertensive renal damage starts in the juxtamedullary cortex (JMC) and gradually extends towards the outer cortex (OC). The intention of the study was to examine if the increase of fibrous tissue in the JMC of the spontaneously hypertensive rat (SHR) is dependent on an increase of collagen synthesis or a decreased collagen breakdown compared to the normotensive control (WKY). Methods and results. The renal damage was evaluated by light microscopy, and the amount of fibrosis was quantified using Sirius red staining. Real-time RT-PCR was used to quantify mRNA for: collagen-type-1-alpha-1 (col1a1), procollagen-n-and -c-proteinase, matrix metalloproteases, MMP-2 and MMP-9, tissue inhibitor of metalloproteases, TIMP-1 and TIMP-2. Western blot was used to quantify the proteins of MMP-2, MMP-9, TIMP-1 and TIMP-2. The relative activities of MMP-2 and MMP-9 were assayed by zymography. The JMC in SHR had an increased amount of collagen as measured by Sirius red, and a 15-fold increase in the mRNA for col1a1. The gene expression of procollagen-c-proteinase was unchanged while procollagen-n-proteinase was increased in SHR and had the highest expression in the JMC. The mRNA for MMP-2 and MMP-9 showed increased expression in SHR, but not specifically in the JMC. Protein analysis showed increased expression for MMP-2 in SHR and in the JMC. MMP-9 protein was lower in SHR. TIMP-1 was increased in SHR at both mRNA and protein level and more so in the JMC. The mRNA and protein analysis of TIMP-2 showed small differences between SHR and WKY.Conclusion. An imbalance of collagen metabolism featuring increased synthesis and inhibition of breakdown favours renal interstitial fibrosis in SHR.

Collagen-binding proteins in age-dependent changes in renal collagen turnover: microarray analysis of mRNA expression

“…It is not clear whether this represents a feature of human aging as such, or if this is the result of comorbidities that have a higher prevalence with increasing age. This is a fact the authors themselves note and a finding that would be more in line with our previous findings in hypertensive rats (7). It may, on the other hand, be the case that the studies represent different stages in the aging process.…”

“…During steady state, there is a balance between collagen synthesis and breakdown in which the latter is achieved by collagenase enzymes including matrix metalloproteases (MMP), MMP-2, 3, and 9 (14). Following kidney injury this equilibrium is disturbed and fibroblasts become activated myofibroblasts to express alpha-smooth muscle actin and large amounts of collagens (7). The occurrence of myofibroblasts is thus considered a key event in the progression to renal fibrosis and chronic renal failure (8,10).…”

Enhanced Matrix Metalloproteinase Activity in the Spontaneously Hypertensive Rat: VEGFR-2 Cleavage, Endothelial Apoptosis, and Capillary Rarefaction

“…The SHR has elevated MMP-9 mRNA [22] compared to the WKY strain. The MMP-9 level is also elevated in stroke [23].…”

TIMP-1 deficiency subverts cell-cycle dynamics in murine long-term HSCs

“…Contrary to what the role of TIMP-1 in inhibiting the prometastatic factor MMP-9 might suggest, high TIMP-1 levels actually correlate with a worse prognosis and a faster progression of the disease. 47,48 This phenomenon seems to be related to the capability of TIMP-1 of promoting cell survival and proliferation of cancer cells, making it an appealing target for novel therapeutic strategies for the treatment of breast cancer, as well as fibrosis secondary to hypertension 49 or liver diseases. 50,51 Although several compounds are currently under investigation as TIMP-1 inhibitors, the potential side effects of such therapeutic approaches are still controversial and poorly investigated.…”