title: Role of matrix metalloproteinase-9 in chronic kidney disease: a new biomarker of resistant albuminuria.
abstract: Resistant albuminuria, developed under adequate chronic blockade of the renin-angiotensin system, is a clinical problem present in a small number of patients with chronic kidney disease (CKD). The mechanism underlying this resistant albuminuria remains unknown. Matrix metalloproteinases (MMPs) are involved in the pathophysiology of cardiovascular and renal diseases. In the present study we tested the role of MMPs in resistant albuminuria. First we evaluated gelatinase MMP-2 and MMP-9 activity by zymography in the Munich Wistar Frömter (MWF) rat, a model of progressive albuminuria, and subsequently in patients with resistant albuminuria. Markers of oxidative stress were observed in the kidneys of MWF rats, together with a significant increase in pro-MMP-2 and active MMP-9 forms. These changes were normalized together with reduced albuminuria in consomic MWF-8(SHR) rats, in which chromosome 8 of MWF was replaced with the respective chromosome from spontaneously hypertensive rats. The MMP-2 and MMP-9 protein levels were similar in patients with normal and resistant albuminuria; however, high circulating levels of collagen IV, a specific biomarker of tissue collagen IV degradation, were observed in patients with resistant albuminuria. These patients showed a significant increase in gelatinase MMP-2 and MMP-9 activity, but only a significant increase in the active MMP-9 form quantified by ELISA, which correlated significantly with the degree of albuminuria. Although the expression of the tissue inhibitor of MMP-9 (TIMP)-1 was similar, a novel AlphaLISA assay demonstrated that the MMP-9-TIMP-1 interaction was reduced in patients with resistant albuminuria. It is of interest that oxidized TIMP-1 expression was higher in patients with resistant albuminuria. Therefore, increased circulating MMP-9 activity is associated with resistant albuminuria and a deleterious oxidative stress environment appears to be the underlying mechanism. These changes might contribute to the progression of CKD in these patients.
authors.affiliation: Unidad de Hipertensión, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain Instituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense de Madrid, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Pulido-Olmo
authors.affiliation: Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Plablo, Madrid, Spain.
authors.forename: Concha F
authors.initials: CF
authors.lastname: García-Prieto
authors.affiliation: Department of Immunology, IIS-Fundación Jimenez Diaz, UAM, Madrid, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Álvarez-Llamas
authors.affiliation: Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain.
authors.forename: María G
authors.initials: MG
authors.lastname: Barderas
authors.affiliation: Department of Immunology, IIS-Fundación Jimenez Diaz, UAM, Madrid, Spain Department of Biochemistry and Molecular Biology, Universidad Complutense de Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Vivanco
authors.affiliation: Instituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense de Madrid, Spain Departamento de Bioquímica, Facultad de Farmacia, Universidad Complutense de Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Aranguez
authors.affiliation: Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Plablo, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Somoza
authors.affiliation: Unidad de Hipertensión, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Segura
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
authors.affiliation: Unidad de Hipertensión, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain Instituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense de Madrid, Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: Fernández-Alfonso
authors.affiliation: Unidad de Hipertensión, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain Departamento de Salud Pública y Medicina Preventiva, Universidad Autónoma de Madrid, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruilope
authors.affiliation: Unidad de Hipertensión, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain Instituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense de Madrid, Spain (gemaruiz@h12o.es).
authors.forename: Gema
authors.initials: G
authors.lastname: Ruiz-Hurtado
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000097:blood / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D004351:Drug Resistance; D005260:Female; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011485:Protein Binding; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: albuminuria; metalloproteinase; oxidative stress; remodelling; renin–angiotensin system