Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell cycle regulation in diabetic nephropathy. Renal hypertrophy is one of the earliest abnormalities of diabetic nephropathy. Although selected cell populations. such as tubulointerstitial fibroblasts, may undergo sustained proliferation in the diabetic environment, most renal cells such as mesangial cells are arrested in the G1-phase of the cell cycle after actively leaving G0-phase and some self-limited early proliferation. High glucose, transforming growth factor-beta (TGF-beta), angiotensin II, and probably other factors induce inhibitors of cyclin-dependent kinases (CDK) including p21Cip1 and p27KiP1. These CDK-inhibitors bind to and inactivate G1-phase cyclin/CDK complexes. The consequence is a lack in kinase activity, underphosphorylation of the retinoblastoma gene protein, and a failure to initiate the G1-S-phase transit. The half-life of CDK-inhibitors may also be increased by serine phosphorylation mediated through activated MAP kinases. Treatment of diabetic rats with angiotensin-converting enzyme inhibitors attenuates glomerular hypertrophy and abolishes the glomerular expression of the CDK-inhibitors p16INK4 and p27KiP1, thus indicating that the cell cycle arrest can be therapeutically influenced. Cell cycle proteins may also be involved in these molecular events, leading to a limited degree of tubular apoptosis, which is a feature of diabetic nephropathy. Although not definitively proven, accumulating evidence suggests that early hypertrophy of renal cells may act as pacemaker for subsequent irreversible structural changes, such as glomerulosclerosis and tubulointerstitial fibrosis. Therefore, a better understanding of altered processes of cell cycle regulation is necessary to develop novel therapeutic strategies to prevent diabetic nephropathy. The recent observation that glomerular hypertrophy and proteinuria do not develop in diabetic p21CiP1 knockout mice indicates that this approach is feasible.
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PMID:Cell cycle regulation in diabetic nephropathy. 1099 92

The zucker diabetic fatty (ZDF-fa/fa) rat is one of the attractive models for type II diabetes based on impaired glucose tolerance caused by the inherited insulin-resistance gene fa. Characterization of nephropathy in this model may provide useful insights into the mechanism of the progression of diabetic nephropathy. The present study analyzed the pathophysiology of diabetes and nephropathy, including the process of glomerulosclerosis in this model by biochemical and morphometric analyses. In addition, we conducted studies in podocytes in culture to examine the direct effects of high glucose on podocytes. ZDF-fa/fa rats showed overt diabetes despite hyperinsulinemia as early as 3 months of age. Blood glucose levels increased further with a considerable decrease of insulin levels at 5 months. Glomerular filtration rate (GFR) was significantly elevated until 3 months, but fell to the level seen in lean rats by 7 months. Proteinuria started to rise during the period of increased GFR, and increased further after GFR had fallen to within the normal range. Renal fibronectin, collagen iv, and vascular endothelial growth factor mRNA levels were increased at 7 months. Glomerulosclerosis commenced as early as 5 months of age, and was associated with glomerular hypertrophy and mild mesangial expansion with evidence of accentuated podocyte injury, as revealed by increased expression of desmin. Electron microscopy suggested that degeneration of podocytes and the development of tuft adhesions were responsible for the glomerular sclerosis in this model. In addition, glomeruli from the diabetic rats showed up-regulation of the cyclin kinase inhibitors, p21 and p27. Further studies suggested that the increase in p27 expression was predominantly caused by podocytes, because predominant immunolocalization of p27 in podocytes in diabetic rats and high glucose medium induced cell hypertrophy accompanied by p27 up-regulation in differentiated podocyte cell lines. In conclusion, progressive diabetic nephropathy in ZDF-fa/fa rats is associated with evidence of podocyte injury. High concentrations of ambient glucose induced podocyte hypertrophy and stress in vitro, suggesting that the podocyte is a likely target of the diabetic milieu.
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PMID:Podocyte injury promotes progressive nephropathy in zucker diabetic fatty rats. 1179 23

p57Kip2, a potent inhibitor of several cyclin/cyclin dependent kinase complexes (CDK ), is a paternally imprinted gene in both humans and mice, and here we show that pregnant mice which are heterozygous for p57Kip2 deficiency display symptoms similar to preeclampsia. p57-/+ (heterozygotes for p57Kip2 ) female mice that were mated with p57-/+ males showed hypertension, proteinuria, thrombocytopenia, decreased anti-thrombin III activity, and increased endothelin levels during late pregnancy. In their kidneys, endotheliosis of glomeruli were recognized along with fibrinoid or hyalinoid deposits. These characteristics were also observed in pregnant p57-/+ females that were mated with wild type males, but not in pregnant wild type females mated with p57-/+ males or wild type males. The pregnant p57-/+ mice had conceptuses both with and without p57Kip2 expression. The conceptuses without p57Kip2 expression showed trophoblastic hyperplasia, which mimics the hallmark proliferation of intermediate trophoblasts in clinical preeclampsia. It is suggested that the preeclampsia-like symptoms of the pregnant p57-/+ mice might have been induced by the conceptus(es) without p57Kip2 expression. In addition, pregnant p57-/+ mice might serve as a new animal model for preeclampsia characterized by trophoblastic hyperplasia.
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PMID:Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice. 1246 47

Podocytes are highly differentiated cells that play a central role in glomerular function. Cell cycle quiescence sustained by the tight regulation of cell cycle molecules seems to be the basis of podocyte differentiation, as reflected in reciprocal expression of cyclins and cyclin kinase inhibitors (CKIs) during glomerulogenesis, concurrent with the expression of podocyte-specific markers. In addition, cell cycle re-entry by podocytes, accompanied by down-regulation of CKIs, leads to either nuclear division without cytokinesis or to marked cell proliferation, both of which result in heavy proteinuria and progressive glomerulosclerosis. These observations suggest that proper cell cycle regulation in podocytes is pivotal for their role in glomerular function and that dysregulation of this system plays a role in glomerular pathology. This review discusses the role of cell cycle molecules in the differentiation, function, and pathology of podocytes.
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PMID:Podocytes, parietal cells, and glomerular pathology: the role of cell cycle proteins. 1248 82

Studies have shown that lipoxin A(4) (LXA(4)) inhibited proliferation of mesangial cells in vitro induced by platelet-derived growth factor, epidermal growth factor, leukotriene D(4) or tumor necrosis factor-alpha. In this study, we investigated the protective effects of 15(R/S)-methyl-LXA(4) on mesangioproliferative nephritis in rats and the signal transduction involved in actions of 15(R/S)-methyl-LXA(4). Mesangioproliferative nephritis was induced by a single intravenous injection of the mouse monoclonal anti-Thy1.1 antibodies. The nephritic rats were treated by intravenous injection of 15(R/S)-methyl-LXA(4) every 8h until the rats were sacrificed. There were increments in glomerular infiltration of leukocytes, expressions of protein and mRNA of interleukin (IL)-1beta and IL-6, activities of nuclear factor-kappaB (NF-kappaB) in nephritic rats from day 1 to 4 after induction of nephritis. The enhanced proteinuria, proliferation score of mesangial cells, glomerular proliferating cell nuclear antigen (PCNA) positive cells, activities of phosphorylated phosphoinositide 3-kinase (PI3-K), Akt(1), alpha-smooth muscle actin (alpha-SMA) and signal transducer and activator of transcription 3(STAT(3)), and reduced expression of p27(kip1) were found on day 4 after induction of nephritis. Treatment of nephritic rats with 15(R/S)-methyl-LXA(4) significantly reduced the protenuria, glomerular infiltration of leukocyte, expressions of protein and mRNA of IL-1beta and IL-6, proliferation score of mesangial cells, glomerular PCNA positive cells, activities of phosphorylated PI3-K, Akt(1), alpha-SMA, NF-kappaB and STAT(3), and ameliorated the decrement in p27(kip1) induced by anti-Thy1.1 antibodies. Protective effects of 15(R/S)-methyl-LXA(4) on nephritis induced by anti-Thy1.1 antibodies were related to PI3-K/Akt(1)/p27(kip1)/cyclin pathway, STAT(3) and NF-kappaB pathway-dependent signal transduction.
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PMID:Signal transduction involved in protective effects of 15(R/S)-methyl- lipoxin A(4) on mesangioproliferative nephritis in rats. 1732 90

The glomerular visceral epithelial cell, or podocyte, is a highly specialized and terminally differentiated cell that is fundamental to the integrity of the glomerular filtration barrier and functions to prevent urinary protein leakage and to oppose intracapillary hydrostatic pressure. Common to many human kidney diseases and experimental animal models is a strong association between podocyte injury and the development of progressive kidney disease. Studies have shown that a decline in podocyte number strongly correlates with, and likely underlies, proteinuria and the progression to glomerulosclerosis. Maintenance of podocyte differentiation, essential to its normal structure and function, is challenged in the setting of glomerular injury, with very divergent outcomes dependent upon the inciting injury. In response to injury, podocytes may undergo several cell fates, including proliferation, de-differentiation, hypertrophy, apoptosis, or necrosis. Common to these potential outcomes of renal injury is their ultimate regulation at the level of the cell cycle. Positive regulators (cyclins and cyclin-dependent kinases) and negative regulators (cyclin-dependent kinase inhibitors) coordinate the cell cycle. There is now a large body of literature confirming the importance of cell cycle regulatory proteins in the cellular response to injury. Emerging lessons from mouse knockout experiments highlight that the cell cycle machinery operates differently in distinct cell types. Recent studies focusing on the roles of cell cycle regulatory proteins specifically in podocytes have provided important clues on how these proteins operate to constrain cell proliferation and preserve differentiation in health, and how they modulate the dysregulated phenotype in diseased states. In disease, both a failure to regenerate lost podocytes and an inappropriate proliferative response can have profound consequences for glomerular structure and function. Here, we will review the latest advances in understanding the roles of cell cycle regulatory proteins in diseases of the podocyte.
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PMID:Cell cycle regulatory proteins in podocyte health and disease. 1757 Sep 40

Preeclampsia is the development of new-onset hypertension with proteinuria after 20 weeks of gestation. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) is a severe form of preeclampsia with high rates of neonatal and maternal morbidity. In recent years, loss of function of cdkn1c (a tight-binding inhibitor of G1 cyclin/cyclin-dependent kinase complexes and a negative regulator of cell proliferation) has been observed in several mouse models of preeclampsia. In this paper, we report on three women with HELLP/preeclampsia who had children with Beckwith Wiedemann syndrome, a complex genetic disorder characterised, among other findings, by overgrowth, omphalocele and macroglossia. All three children displayed mutations in CDKN1C predicted to generate truncated proteins. Two of the mutations were maternally inherited while the third was de novo. This finding suggests a fetal contribution to the maternal disease. To the best of our knowledge this is the first report of CDKN1C mutations in children born to women with preeclampsia/HELLP syndrome, thus suggesting the involvement of an imprinted gene in the pathophysiology of preeclampsia.
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PMID:CDKN1C mutations in HELLP/preeclamptic mothers of Beckwith-Wiedemann Syndrome (BWS) patients. 1938 58