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Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function.

ABSTRACT: Recent studies indicate that the Notch signaling pathway plays an important role in the development of diabetic kidney disease and focal segmental glomerulosclerosis (FSGS). Here we analyzed the degree of expression and localization of Notch ligands (Jagged1 and Delta1) and activated (cleaved) receptors (Notch1 and Notch2) in healthy human kidneys and in renal biopsies from a wide variety of kidney diseases. These included patients with minimal change disease, membranous nephropathy, lupus nephritis ISN/RPS classes III/IV/V, hypertensive nephrosclerosis, crescentic glomerulonephritis, tubulointerstitial fibrosis, IgA nephropathy, diabetic kidney disease, and FSGS. We found that cleaved Notch1, Notch2, and Jagged1 are expressed on podocytes in proteinuric nephropathies and their level of expression correlated with the amount of proteinuria across all disease groups. The degree of glomerulosclerosis correlated with podocyte expression of cleaved Notch1, while the severity of tubulointerstitial fibrosis and the estimated glomerular filtration rate correlated with expression of cleaved Notch1 in the tubulointerstitium. Hence, our results raise the possibility that Notch pathway activation is a common mechanism in the pathophysiology of a wide range of acquired renal diseases.

SUBMITTER: Murea M

PROVIDER: S-EPMC3164583 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function.

Murea Mariana M Park Jun-Ki JK Sharma Shuchita S Kato Hideki H Gruenwald Antje A Niranjan Thiruvur T Si Han H Thomas David B DB Pullman James M JM Melamed Michal L ML Susztak Katalin K

Kidney international 20100609 5

Recent studies indicate that the Notch signaling pathway plays an important role in the development of diabetic kidney disease and focal segmental glomerulosclerosis (FSGS). Here we analyzed the degree of expression and localization of Notch ligands (Jagged1 and Delta1) and activated (cleaved) receptors (Notch1 and Notch2) in healthy human kidneys and in renal biopsies from a wide variety of kidney diseases. These included patients with minimal change disease, membranous nephropathy, lupus nephr ...[more]

PMID: 20531454

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Project description:Background and objectivesDiabetes mellitus is associated with increased risk of cognitive impairment. This study examines whether microvascular disease, as measured by albuminuria and decline in estimated GFR (eGFR), is associated with cognitive decline during 3.3 years of follow-up in individuals with diabetes with a normal baseline eGFR (approximately 90 ml/min per 1.73 m(2)).Design, setting, participants, & measurementsParticipants were from the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes study (N=2977; mean age 62.5 ± 5.8 years; recruitment from August 2003 to December 2005, followed through June 2009), which examined the association of intensive versus standard glucose control on cognitive function. Participants underwent three neuropsychologic tests at baseline, 20 months, and 40 months. Tests included information processing speed, verbal memory, and executive function. Mixed-effects models were used to assess the association of albuminuria and eGFR on the percentage decline in each test.ResultsParticipants with albuminuria at baseline and follow-up (persistent albuminuria) (-5.8% [95% confidence interval (CI), -7.3 to -4.2]) and participants with albuminuria at follow-up but none at baseline (progressive albuminuria) (-4.1% [95% CI, -5.6 to -2.7]) had greater percentage declines on information processing speed than participants without albuminuria at baseline and at follow-up (no albuminuria) (-2.6% [95% CI, -3.4 to -1.9]) (P=0.001 and P=0.10, respectively). There were borderline percentage changes in the test of verbal memory (4.8% [95% CI, 2.4 to 7.1] and 4.7% [95% CI, 2.5 to 7.0] versus 7.1% [95% CI, 6.0 to 8.3]; P=0.11 and P=0.08, respectively). On logistic regression analysis, persistent albuminuria (odds ratio, 1.37 [95% CI, 1.09 to 1.72]) and progressive albuminuria (odds ratio, 1.25 [95% CI, 1.02 to 1.56]) were associated with a ≥ 5% decline in information processing speed scores but not with verbal memory or executive function performance. A 1 ml/min per 1.73 m(2) per year eGFR decline had a borderline association with decline in tests of cognitive function.ConclusionsPersistent albuminuria and progressive albuminuria are associated with a decline in cognitive function in relatively young individuals with diabetes with unimpaired eGFR. These findings do not rule out the possibility of other processes causing cognitive decline.

Project description:BACKGROUND:Albuminuria is the early manifestation of the pathogenesis of diabetic nephropathy (DN). The current study was to investigate the relationship of pulmonary function with albuminuria in type 2 diabetic patients with preserved renal function to evaluate the role of pulmonary function in the early stage of DN. METHODS:A total of 326 patients with type 2 diabetes mellitus (T2DM) including 270 without albuminuria and 56 with albuminuria, and 265 non-diabetic patients were enrolled. The patients' general information, and the parameters of pulmonary function, including forced vital capacity (FVC), forced expiratory volume in 1?s (FEV1), FEV1/FVC, total lung capacity (TLC), diffusion capacity for carbon monoxide of lung (DLCO) were compared between T2DM and control groups, as well as T2DM patients with and without albuminuria groups. All pulmonary function parameters were expressed as a percentage of those predicted (%pred). Logistic regression models were constructed to test the association of albuminuria and pulmonary function. RESULTS:The values of FVC%pred, FEV1%pred, TLC%pred and DLCO%pred were lower, and the proportion of subjects with FVC%pred <?80, FEV1%pred <?80, and DLCOc%pred <?80 was higher in T2DM subjects than controls (all P?<?0.05). Subgroup analysis of diabetic patients showed that the values of FVC%pred, FEV1%pred, TLC%pred, and DLCOc%pred (97.18?±?13.45, 93.95?±?14.51, 90.64?±?9.97, 87.27?±?13.13, respectively) were significantly lower in T2DM subjects with albuminuria than those without albuminuria (103.94?±?14.12, 99.20?±?14.25, 93.79?±?10.36, 92.62?±?13.45, all P?<?0.05). There was a significantly negative correlation between the urine albumin-to-creatinine ratio (UACR) and DLCOc%pred (r =?-?0.143, P =?0.010) in spearman linear correlation test. In logistic regression analysis, the FVC%pred (OR 0.965, 95%CI 0.944-0.988), FEV1%pred (OR 0.975, 95%CI 0.954-0.996), and DLCOc%pred (OR 0.974, 95%CI 0.951-0.998) were independently associated with albuminuria after adjustments for smoking index, duration, HbA1c, FBG, and TG. CONCLUSION:Our results demonstrated albuminuria is associated with a restrictive pulmonary function as well as pulmonary diffusion function in T2DM with preserved renal function, which remind us to be alert of the pulmonary function decline even in the early stage of DN.

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Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function.

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Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function.

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