Prepubertal onset of diabetes prevents expression of renal cortical connective tissue growth factor
ABSTRACT Puberty unmasks or accelerates the nephropathy of diabetes mellitus (DM). We performed focused microarray analysis to test the hypothesis that one or more genes in the transforming growth factor beta (TGF-beta) signaling system would be differentially regulated in male rats depending on their age at onset of DM. Littermates were started on the 6-week protocol at 4 weeks or 14 weeks of age. Renal cortical RNA was isolated and analyzed using gene chips with more than 30,000 transcripts. Age-specific effects of DM were demonstrated for 1,760 transcripts. Analysis then focused on 89 genes involved in the TGF-beta signaling pathway. Three of these genes showed age-dependent responses to DM, confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Connective tissue growth factor (CTGF) mRNA and protein were both increased approximately 30% in the renal cortex 6 weeks after adult-onset DM, with no alteration in either parameter after juvenile onset. Follistatin and avian myelocytomatosis viral oncogene homolog mRNA both showed a similar age-related pattern of response to DM, but protein levels did not parallel mRNA for either of these gene products. Given the known roles of CTGF in progressive nephropathies, it is an attractive candidate to explain pubertal acceleration or unmasking of the kidney disease of diabetes.
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ABSTRACT: Impaired kidney function is a well-recognized complication following liver transplantation (LT). Studies of this complication in children have been limited by small numbers and insensitive outcome measures. Our aim was to define the prevalence of, and identify risk factors for, post-LT kidney dysfunction in a multicenter pediatric cohort using measured glomerular filtration rate (mGFR). We conducted a cross-sectional study of 397 patients enrolled in the Studies in Pediatric Liver Transplantation (SPLIT) registry, using mGFR < 90 mL/min/1.73 m(2) as the primary outcome measure. Median age at LT was 2.2 years. Primary diagnoses were biliary atresia (44.6%), fulminant liver failure (9.8%), metabolic liver disease (16.4%), chronic cholestatic liver disease (13.1%), cryptogenic cirrhosis (4.3%) and other (11.8%). At a mean of 5.2 years post-LT, 17.6% of patients had a mGFR < 90 mL/min/1.73 m(2) . In univariate analysis, factors associated with this outcome were transplant center, age at LT, primary diagnosis, calculated GFR (cGFR) at LT and 12 months post-LT, primary immunosuppression, early post-LT kidney complications, age at mGFR, height and weight Z-scores at 12 months post-LT. In multivariate analysis, independent variables associated with a mGFR <90 mL/min/1.73 m(2) were primary immunosuppression, age at LT, cGFR at LT and height Z-score at 12 months post-LT.American Journal of Transplantation 12/2010; 10(12):2673-82. DOI:10.1111/j.1600-6143.2010.03316.x · 5.68 Impact Factor
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ABSTRACT: The advanced glycation end‑product (AGE)‑receptor for AGE (RAGE) axis induces transforming growth factor‑β (TGF‑β) expression, cell hypertrophy and increases extracellular matrices that are indicated in the pathogenesis of diabetic nephropathy (DN). RAGE binds to numerous ligands besides AGE, including S100B. In the present study, the roles of S100B in high glucose‑induced p21WAF1, extracellular matrices, TGF‑βl and cell hypertrophy in mouse mesangial (MES13) cells were investigated. High glucose (30 mM) time‑dependently (24‑72 h) induced S100B expression. High glucose and exogenous S100B (1 µM) time‑dependently increased p21WAF1 gene transcription and protein expression, increased type IV collagen and fibronectin protein expression, and TGF‑β gene transcription and bioactivity. Exogenous S100B also time‑dependently activated the extracellular regulated kinases (ERK1/2), p38 kinase and c‑Jun N‑terminal kinase (JNK) signaling pathways. Exogenous S100B‑induced TGF‑β gene transcription and bioactivity were attenuated by SB203580 (p38 kinase inhibitor) and PD98059 (ERK1/2 inhibitor). Finally, the knockdown of S100B by small interfering RNA (siRNA) attenuated high glucose‑induced TGF‑β gene transcription and bioactivity, type IV collagen and fibronectin protein expression and p21WAF1 protein expression. Thus, S100B induced TGF‑β via the ERK1/2 and p38 kinase pathways in mesangial cells. Additionally, high glucose‑induced pro‑fibrotic genes (TGF‑β, type IV collagen and fibronectin) and cell hypertrophy‑related p21WAF1 are dependent on S100B.International Journal of Molecular Medicine 12/2014; 35(2). DOI:10.3892/ijmm.2014.2024 · 2.09 Impact Factor