Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term exposure to cadmium (Cd) induces perturbation of kidney proximal tubular epithelial cells. Mitochondrial dysfunction in renal cortical cells may contribute to the pathogenesis of Cd-induced nephropathy. In this study, we examined the accumulation of mitochondrial DNA (mtDNA) with a large deletion and cellular senescence in the renal cortex. Wistar rats at 8 weeks of age were intraperitoneally injected with 1 mL of 1 mM CdCl(2) or saline, 3 times/week for 5, 20, 40, or 80 weeks. Mitochondrial Cd content in the renal cortex was quantified by atomic absorption analysis. Cytochrome c oxidase (CCO) and senescence-associated beta-galactosidase (SA-beta-gal) activity were determined in renal cortex by enzyme-histochemistry. mtDNA in total DNA extracted from the renal cortex was amplified by PCR, and mtDNA deletions, including 4,834-bp (nt8118-nt12937) deletion, were determined and semiquantified. After 40 weeks of Cd injection, Cd levels in the renal cortex reached a saturation level, and 30% of the level of the whole-cell fraction was found in the mitochondria. CCO activity in the renal cortex, which was predominantly found in proximal tubular cells, decreased after 40 weeks of Cd exposure. Expression of SA-beta-gal was detected primarily in the proximal tubular cells and significantly increased after 80 weeks of Cd exposure. After 40 weeks of study, accumulation of 4,834-bp deletion in mtDNA was evident in both groups of rats; however, the amount of the deletion was significantly greater in Cd-treated rats than in control rats. Our results indicate that long-term Cd exposure induced a post-regenerative state of proximal tubular cells, which accelerated accumulation of 4,834-bp mtDNA deletions in the renal cortex, suggesting that Cd may be a senescence acceleration factor for kidney proximal tubular epithelial cells, which results in Cd-induced nephropathy.
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PMID:Cadmium-induced nephropathy in rats is mediated by expression of senescence-associated beta-galactosidase and accumulation of mitochondrial DNA deletion. 1512 10

The glomerular filtration barrier separates the blood from the urinary space. Nephrin is a transmembrane protein that belongs to the immunoglobulin superfamily and is localized to the slit diaphragms that are a critical component of this filtration barrier. Mutations in the nephrin gene (NPHS1) lead to congenital Finnish nephropathy, whereas alterations in the level of nephrin expression have been identified in a wide range of acquired glomerular diseases. A 186-bp fragment from the human NPHS1 promoter is capable of directing podocyte-specific expression of a beta-galactosidase transgene when placed in front of a heterologous minimal promoter in transgenic mice. The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner. Taken together, these results suggest that WT1 may be required for regulation of the NPHS1 gene in vivo.
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PMID:WT1 activates a glomerular-specific enhancer identified from the human nephrin gene. 1550 38

Diabetic nephropathy is the commonest cause of end-stage renal disease. Inordinate kidney growth and glomerular hyperfiltration at the very early stages of diabetes are putative antecedents to this disease. The kidney is the only organ that grows larger with the onset of diabetes mellitus, yet there remains confusion about the mechanism and significance of this growth. Here we show that kidney proximal tubule cells in culture transition to senescence in response to oxidative stress. We further determine the temporal expression of G(1) phase cell cycle components in rat kidney cortex at days 4 and 10 of streptozotocin diabetes to evaluate changes in this growth response. In diabetic rats we observe increases in kidney weight-to-body weight ratios correlating with increases in expression of the growth-related proteins in the kidney at day 4 after induction of diabetes. However, at day 10 we find a decrease in this profile in diabetic animals coincident with increased cyclin-dependent kinase inhibitor expressions. We observe no change in caspase-3 expression in the diabetic kidneys at these early time points; however, diabetic animals demonstrate reduced kidney connexin 43 and increased plasminogen activator inhibitor-1 expressions and increased senescence-associated beta-galactosidase activity in cortical tubules. In summary, diabetic kidneys exhibit an early temporal induction of growth phase components followed by their suppression concurrent with the induction of cyclin-dependent kinase inhibitors and markers of senescence. These data delineate a phenotypic change in cortical tubules early in the pathogenesis of diabetes that may contribute to further downstream complications of the disease.
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PMID:Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. 2050 38

We have reported a possible involvement of apurinic/apyrimidinic endonuclease 1 (APE1), one of the DNA repair pathways, in various nephropathy models and found that there is a close connection between APE1 and p53-dependent apoptosis. Therefore, we investigated the changes of APE in aging rat kidney since aging is the consequence of increased susceptibility to apoptosis and impaired repair. Characteristics of chronological aging were compared among 6-, 24- and 28-month-old male Sprague-Dawley rats. Serum blood urea nitrogen and creatinine were measured for renal function. Western blot assay was compared for p53, bax, cleaved caspase 3, rH2AX, and APE1. Immunohistochemical staining of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and APE1 was performed. Cellular senescence was checked by beta-galactosidase staining. Compared with young rats, aged rats showed significant increase in creatinine level with cellular senescence in the proximal convoluted tubules confirmed by beta-galactosidase staining. All the checked variables were significantly increased with aging: 1) increased p53, bax, and caspase 3 may activate the apoptotic pathway, 2) increased rH2AX and 8-OHdG immunolocalization in the proximal convoluted tubules might mean augmented DNA damage, and 3) increased APE1 might be caused by the immunoreactivity in the distal convoluted tubules while decreased in the proximal convoluted tubules. These results suggested that APE1 might have little protective effects on p53-dependent apoptosis irrespective of DNA repair activities in aged renal proximal tubules. Therefore, researchers should use older animals than 24-month-old rats in future studies for investigating the relationship between the apoptosis and DNA repair in the aging kidneys.
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PMID:Apurinic/apyrimidinic endonuclease 1 on aging-associated deteriorations in rat kidneys. 2536 96


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