Angiotensin-II induced hypertension and renovascular remodelling in tissue inhibitor of metalloproteinase 2 knockout mice

Abstract

Sustained hypertension induces renovascular remodeling by altering extracellular matrix (ECM) components. Matrix metalloproteinases (MMPs) are Zn-dependent enzymes that regulate ECM turnover in concert with their inhibitors, tissue inhibitors of metalloproteinases, TIMPs. Increased MMP-2 & -9 have been implicated in hypertensive complications; however, the contribution of individual MMPs/TIMPs in renal remodeling has not been fully elucidated. The purpose of this study was to determine the effect of TIMP2 deficiency and thus MMP-2 on Ang-II induced renal remodeling. C57BL/6J (WT) and TIMP2 knockout mice were infused with Angiotensin-II (Ang-II) at 250 ng. kg-1. min-1 for 4 weeks. Blood pressure was measured weekly and end-point laser Doppler flowmetry was done to assess cortical blood flow. Immunohistochemical staining was performed for collagen and elastin analyses. The activity of MMP-9, and -2 was determined by Gelatin zymography. Ang-II induced similar elevation in mean blood pressure in TIMP2-/- and WT mice. In TIMP2-/- mice, Ang-II treatment was associated with a greater reduction in renal cortical blood flow and barium angiography demonstrated decreased vascular density compared to Ang-II treated WT mice. Peri-glomerular and vascular collagen deposition was increased and elastin content was decreased causing increased wall-to-lumen ratio in TIMP2-/- mice compared to WT mice receiving Ang-II. Ang-II increased the expression and activity of MMP-9 predominantly in TIMP2-/- mice than in WT mice. These results suggest that TIMP2 deficiency exacerbates renovascular remodeling in agonist induced hypertension by a mechanism which may, in part, be attributed to increased activity of MMP-9.

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

“…TIMP-2 mostly inhibits pro-MMP-2 [53]. Although TIMP-2 is a major MMP-2 inhibitor, TIMP-2 also facilitates the activation of proMMP-2 via a cell membrane anchored membrane type 1 metalloproteinase (MT-1-MMP) [11, 54]. Increased expressions of both TIMPs have been associated with glomerulosclerosis [1, 55].…”

“…While TIMP-1 inhibits MMP-9, TIMP-2 is the main inhibitor of MMP-2. Enhanced expressions of both TIMPs have been linked with glomerulosclerosis [1, 11, 55]. TIMP-2 in interaction with MT-1-MMP facilitates the activation of pro-MMP-2 [11, 54].…”

“…Enhanced expressions of both TIMPs have been linked with glomerulosclerosis [1, 11, 55]. TIMP-2 in interaction with MT-1-MMP facilitates the activation of pro-MMP-2 [11, 54]. TIMP-2 and TIMP-3 play differential and contrasting roles in renal injury in rodent models: TIMP-3 protects from damage, whereas TIMP-2 promotes injury through MMP-2 activation [87].…”

“…Secreted MMP-2 is bound to the tissue inhibitor of MMP 2 (TIMP-2) [72]. This binding occurs between the hemopexin domain of MMP-2 and the noninhibitory C terminal domain of TIMP-2 [11]. Thereafter, the activation of proMMP-2 can be induced by gelatinases MMP-2 or MMP-9 [73, 74].…”

“…In general, all MMPs are inhibited by TIMPs. The mechanism of TIMP inhibition encompasses the binding of N-terminal domain to the catalytic site of the MMPs, where a cysteine-chelating group inactivates the catalytic zinc site with an N-terminal amino and carbonyl group [1, 11](Fig. 1).…”