Angiotensin-II induced hypertension and renovascular remodelling in tissue inhibitor of metalloproteinase 2 knockout mice.
BACKGROUND
Sustained hypertension induces renovascular remodelling 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 and MMP-9 have been implicated in hypertensive complications; however, the contribution of individual MMPs/TIMPs in renal remodelling has not been fully elucidated. The purpose of this study was to determine the effect of TIMP2 deficiency and thus MMP-2 on angiotensin-II (Ang-II) induced renal remodelling.


METHODS
C57BL/6J (wild-type) and TIMP2 knockout mice were infused with Ang-II at 250 ng/kg per min 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 MMP-2 was determined by Gelatin zymography.


RESULTS
Ang-II induced similar elevation in mean blood pressure in TIMP2 and wild-type 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 with Ang-II treated wild-type mice. Peri-glomerular and vascular collagen deposition was increased and elastin content was decreased causing increased wall-to-lumen ratio in TIMP2 mice compared with wild-type mice receiving Ang-II. Ang-II increased the expression and activity of MMP-9 predominantly in TIMP2 mice than in wild-type mice.


CONCLUSIONS
These results suggest that TIMP2 deficiency exacerbates renovascular remodelling in agonist-induced hypertension by a mechanism that may, in part, be attributed to increased activity of MMP-9.
aDepartment of Physiology and Biophysics bRobley Rex VA Medical Center cDivision of Nephrology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Sathnur
S
Pushpakumar
Sourav
S
Kundu
Tyranny
T
Pryor
Srikanth
S
Givvimani
Eleanor
E
Lederer
Suresh C
SC
Tyagi
Utpal
U
Sen
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D062186:Arterial Pressure; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000032:analysis; D004549:Elastin / Q000032:analysis; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000172:deficiency* / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D019714:Tissue Inhibitor of Metalloproteinases; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D004549:Elastin; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9