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A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy.

ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1) has been implicated in renal fibrosis. In vitro, PAI-1 inhibits plasmin generation, and this decreases mesangial extracellular matrix turnover. PAI-1R, a mutant PAI-1, increases glomerular plasmin generation, reverses PAI-1 inhibition of matrix degradation, and reduces disease in experimental glomerulonephritis. This study sought to determine whether short-term administration of PAI-1R could slow the progression of glomerulosclerosis in the db/db mouse, a model of type 2 diabetes in which mesangial matrix accumulation is evident by 20 wk of age. Untreated uninephrectomized db/db mice developed progressive albuminuria and mesangial matrix expansion between weeks 20 and 22, associated with increased renal mRNA encoding alpha1(I) and (IV) collagens and fibronectin. Treatment with PAI-1R prevented these changes without affecting body weight, blood glucose, glycosylated hemoglobin, creatinine, or creatinine clearance; therefore, PAI-1R may prevent progression of glomerulosclerosis in type 2 diabetes.

SUBMITTER: Huang Y

PROVIDER: S-EPMC2396741 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy.

Huang Yufeng Y Border Wayne A WA Yu Ling L Zhang Jiandong J Lawrence Daniel A DA Noble Nancy A NA

Journal of the American Society of Nephrology : JASN 20080123 2

Plasminogen activator inhibitor-1 (PAI-1) has been implicated in renal fibrosis. In vitro, PAI-1 inhibits plasmin generation, and this decreases mesangial extracellular matrix turnover. PAI-1R, a mutant PAI-1, increases glomerular plasmin generation, reverses PAI-1 inhibition of matrix degradation, and reduces disease in experimental glomerulonephritis. This study sought to determine whether short-term administration of PAI-1R could slow the progression of glomerulosclerosis in the db/db mouse, ...[more]

PMID: 18216319

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Project description:Malnutrition and immunologic derangement were not uncommon in patients with chronic kidney disease (CKD). However, the long-term effects of prognostic nutritional index (PNI), an immunonutrition indictor, on renal outcomes in patients with diabetic nephropathy (DN) and type 2 diabetes mellitus (T2DM) are unknown. In this retrospective cohort study, 475 patients with T2DM and biopsy-confirmed DN from West China Hospital between January 2010 and September 2019 were evaluated. PNI was evaluated as serum albumin (g/L) + 5 × lymphocyte count (109/L). The study endpoint was defined as progression to end-stage renal disease (ESRD). The Cox regression analysis was performed to investigate the risk factors of renal failure in DN patients. A total of 321 eligible individuals were finally included in this study. The patients with higher PNI had a higher eGFR and lower proteinuria at baseline. Correlation analysis indicated PNI was positively related eGFR (r = 0.325, p < 0.001), and negatively correlated with proteinuria (r = -0.68, p < 0.001), glomerular lesion (r = -0.412, p < 0.001) and interstitial fibrosis and tubular atrophy (r = -0.282, p < 0.001). During a median follow-up of 30 months (16-50 months), the outcome event occurred in 164(51.09%) of all the patients. After multivariable adjustment, each SD (per-SD) increment of PNI at baseline was associated with a lower incidence of ESRD (hazard ratio, 0.705, 95% CI, 0.523-0.952, p = 0.023), while the hypoalbuminemia and anemia were not. For the prediction of ESRD, the area under curves (AUC) evaluated with time-dependent receiver operating characteristics were 0.79 at 1 year, 0.78 at 2 years, and 0.74 at 3 years, respectively, and the addition of PNI could significantly improve the predictive ability of the model incorporating traditional risk factors. In summary, PNI correlated with eGFR and glomerular injury and was an independent predictor for DN progression in patients with T2DM. Thus, it may facilitate the risk stratification of DN patients and contribute to targeted management.

Dataset Information

A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy.

Publications

A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy.

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