RGD Reference Report - Knockout of Matrix Metalloproteinase 2 Opposes Hypertension- and Diabetes-Induced Nephropathy. - Rat Genome Database

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Knockout of Matrix Metalloproteinase 2 Opposes Hypertension- and Diabetes-Induced Nephropathy.

Authors: Hirata, Takashi  Fan, Fan  Fan, Letao  Amin, Ghadir  White, Tiffani  Geurts, Aron M  Kojima, Naoki  Takahashi, Teisuke  Miyata, Noriyuki  Williams, Jan  Roman, Richard J 
Citation: Hirata T, etal., J Cardiovasc Pharmacol. 2023 Aug 25. doi: 10.1097/FJC.0000000000001473.
RGD ID: 401827835
Pubmed: PMID:37643020   (View Abstract at PubMed)
DOI: DOI:10.1097/FJC.0000000000001473   (Journal Full-text)

The progression of chronic kidney disease (CKD) results from the accumulation of extracellular matrix leading to end-stage renal disease. We previously demonstrated that a broad-spectrum metalloproteinase (MMP) inhibitor reduced renal injury in rat models of hypertension and diabetes. However, the isoforms and mechanisms involved are unclear. This study examined the role of MMP2 during the development of proteinuria and renal injury following induction of hypertension or diabetes in Dahl salt-sensitive (SS) and SS MMP2 knockout (KO) rats. Mean arterial pressure (MAP) rose from 115 ± 2 to 145 ± 2 mmHg and 116 ± 1 to 152 ± 3 mmHg in MMP2 KO and SS rats fed a high salt (HS; 8% NaCl) diet for 3 weeks. The degree of proteinuria, glomerular injury, renal fibrosis, and podocyte loss was lower in MMP2 KO than in SS rats. Blood glucose and HbA1c levels, and MAP rose to the same extent in streptozotocin (STZ)-treated SS and MMP2 KO rats. However, the degree of proteinuria, glomerulosclerosis, renal fibrosis, renal hypertrophy, glomerular permeability to albumin and the renal expression of MMP2 and TGFβ1 were significantly reduced in MMP2 KO rats. Glomerular filtration rate (GFR) fell by 33% after 12 weeks of diabetes in STZ-treated SS rats compared to time-control rats, but GFR only fell by 12% in MMP2 KO rats. These results indicate that activation of MMP2 plays an essential role in the pathogenesis of hypertensive and diabetic nephropathy and suggests that an MMP2 inhibitor might slow the progression of CKD.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Diabetic Nephropathies amelioratesISOMmp2 (Rattus norvegicus)401827835; 401827835 RGD 
Diabetic Nephropathies amelioratesIMP 401827835; 401827835; 401827835 RGD 
Hypertensive Nephropathy amelioratesISOMmp2 (Rattus norvegicus)401827835; 401827835 RGD 
Hypertensive Nephropathy amelioratesIMP 401827835; 401827835; 401827835 RGD 
proteinuria amelioratesISOMmp2 (Rattus norvegicus)401827835; 401827835associated with Experimental Diabetes MellitusRGD 
proteinuria amelioratesIMP 401827835; 401827835; 401827835associated with Experimental Diabetes MellitusRGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal podocyte physiology amelioratesIMP 401827835; 401827835; 401827835associated with Experimental Diabetes Mellitus and compared to wild type SSRGD 
decreased circulating creatinine level  IMP 401827835; 401827835; 401827835compared to wild type SSRGD 
decreased kidney weight  IMP 401827835; 401827835; 401827835associated Experimental Diabetes Mellitus more ...RGD 
decreased transforming growth factor beta level  IMP 401827835; 401827835; 401827835compared to wild type SSRGD 
decreased urine protein level  IMP 401827835; 401827835; 401827835compared to wild type SSRGD 
decreased vascular permeability amelioratesIMP 401827835; 401827835; 401827835associated with Experimental Diabetes Mellitus and compared to wild type SSRGD 
glomerulosclerosis amelioratesIMP 401827835; 401827835; 401827835compared to wild type SSRGD 
increased renal glomerular filtration rate  IMP 401827835; 401827835; 401827835compared to wild type SSRGD 
renal interstitial fibrosis amelioratesIMP 401827835; 401827835; 401827835compared to wild type SSRGD 
Objects Annotated

Genes (Rattus norvegicus)
Mmp2  (matrix metallopeptidase 2)
Mmp2em2Mcwi  (matrix metallopeptidase 2; zinc finger nuclease induced mutant 2, Medical College of Wisconsin)

Genes (Mus musculus)
Mmp2  (matrix metallopeptidase 2)

Genes (Homo sapiens)
MMP2  (matrix metallopeptidase 2)

Strains
SS-Mmp2em1Mcwi-/-  (SS-Mmp2em1Mcwi-/Mmp2em1Mcwi-)

Objects referenced in this article
Strain SS-Mmp2em1Mcwi null Rattus norvegicus
Strain SS-Mmp2em2Mcwi+/+ SS-Mmp2em2Mcwi+/Mmp2em2Mcwi+ Rattus norvegicus
Strain SS-Mmp2em2Mcwi-/- SS-Mmp2em2Mcwi-/Mmp2em2Mcwi- Rattus norvegicus
Strain SS-Mmp2em2Mcwi null Rattus norvegicus

Additional Information