RGD Reference Report - Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-gamma. - Rat Genome Database

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Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-gamma.

Authors: Revelo, Monica P  Federspiel, Charles  Helderman, Harold  Fogo, Agnes B 
Citation: Revelo MP, etal., Nephrol Dial Transplant. 2005 Dec;20(12):2812-9. Epub 2005 Oct 12.
RGD ID: 13208600
Pubmed: PMID:16221712   (View Abstract at PubMed)
DOI: DOI:10.1093/ndt/gfi172   (Journal Full-text)


BACKGROUND: Chronic allograft nephropathy (CAN) is a major cause of loss of renal allografts. Mechanisms postulated to be involved include sequelae of rejection, warm ischaemia time, drug toxicity, ongoing hypertension and dyslipidaemia. Plasminogen activator inhibitor-1 (PAI-1) is implicated not only in thrombosis, but also in fibrosis, by inhibiting matrix degradation, and is expressed in renal parenchymal cells as well as in macrophages. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the steroid receptor superfamily, and plays a major beneficial role in lipid regulation, insulin sensitivity and macrophage function, factors that may play a role in CAN. We therefore studied the expression of these molecules in CAN.
METHODS: All renal biopsy/nephrectomy files from Vanderbilt and Nashville VAMC from a 6 year period were reviewed to identify all renal transplant biopsies or nephrectomies more than 6 months after transplant with CAN. CAN was defined as fibrosis in the graft, vascular, interstitial or glomerular. All cases were scored for severity of fibrosis in vasculature (0-3 scale), glomeruli (% affected with either segmental and/or global sclerosis) and interstitial fibrosis (% of sample affected). PAI-1 and PPAR-gamma immunostaining was assessed on a 0-3 scale in glomeruli, vessels and tubules.
RESULTS: Eighty-two patients with a total of 106 samples met entry criteria. The population consisted of 59 Caucasians and 23 African-Americans; 49 males, 33 females with average age 37.9+/-1.7 years. Average time after transplant at time of biopsy was 60.5+/-4.9 months (range 7-229). Glomerulosclerosis extent in CAN was on average 26.5+/-2.4% compared with 3.6+/-1.2% in normal control kidneys from native kidney cancer nephrectomies and 0% in transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN. Native control kidneys showed mild interstitial fibrosis (8.0+/-1.2%), whereas transplant controls showed very minimal fibrosis (2.0+/-2.0%). Interstitial fibrosis in CAN kidneys was on average 47.9+/-2.4%. Glomerular PAI-1 and PPAR-gamma staining scores were markedly increased in CAN (1.8+/-0.1, 2.3+/-0.1, respectively) compared with normal control kidneys from native kidney cancer nephrectomies (PAI-1 0.2+/-0.2 and PPAR-gamma 0.4+/-0.2, P<0.001) and transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN (PAI-1 0 and PPAR-gamma 0, P<0.001). Tubular PAI-1 and PPAR-gamma staining scores were 1.9+/-0.1 and 1.9+/-0.1, respectively, and also increased over both native and transplant kidney controls (0.8+/-0.2 for both categories for PAI-1, 1.2+/-0.2 for both categories for PPAR-gamma, respectively). Vascular sclerosis in CAN was 1.0+/-0.1 with increased PAI-1 and PPAR-gamma scores (1.7+/-0.1, 1.2+/-0.1, respectively) compared with controls. Infiltrating macrophages were increased in CAN, and were positive for both PAI-1 and PPAR-gamma. Biopsies with less sclerosis overall showed a trend for less PAI-1 and PPAR-gamma staining.
CONCLUSION: PAI-1 and PPAR-gamma are both increased in CAN compared with non-scarred native or transplant control kidneys. We speculate that altered matrix metabolism and macrophage function might be involved in the development of CAN.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Chronic Allograft Nephropathy  IEP 13208600; 13208600protein:increased expression:kidney:RGD 
Chronic Allograft Nephropathy  ISOPPARG (Homo sapiens)13208600; 13208600protein:increased expression:kidney:RGD 
Chronic Allograft Nephropathy  ISOSERPINE1 (Homo sapiens)13208600; 13208600protein:increased expression:kidney:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pparg  (peroxisome proliferator-activated receptor gamma)
Serpine1  (serpin family E member 1)

Genes (Mus musculus)
Pparg  (peroxisome proliferator activated receptor gamma)
Serpine1  (serine (or cysteine) peptidase inhibitor, clade E, member 1)

Genes (Homo sapiens)
PPARG  (peroxisome proliferator activated receptor gamma)
SERPINE1  (serpin family E member 1)


Additional Information