Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypercholesterolemia and mesangial cell proliferation have been proposed to play a role in the progression of glomerulosclerosis in diabetic nephropathy and other renal diseases. Although LDL is mitogenic for and cytotoxic to mesangial cells, the effect of HDL on these cells is unknown. HDL stimulates fibroblast mitogenesis and is the principal cholesterol-bearing lipoprotein in the rat, the experimental model for studying the effect of hyperlipidemia on renal disease. Insulin is mitogenic in several cell systems, and its levels are increased in serum in non-insulin-dependent diabetes mellitus. This study investigates whether HDL acts as a growth factor in mesangial cells and whether it functions in parallel with insulin. It was found that HDL at protein concentrations between 10 and 500 microg/ml, both alone and in the presence of 100 nM insulin, increased DNA synthesis in mesangial cells (129 to 165% of control for HDL alone; 140 to 235% for HDL plus insulin), whereas HDL at 1000 microg/ml and greater inhibited mesangial cell proliferation. Insulin alone at 100 nM stimulated [3H]thymidine incorporation in the same cell system (145% of control); the mitogenic effect of insulin was additive to that of HDL. Purified apo A-I had a similar effect, but at significantly lower concentrations. Specific binding of HDL to mesangial cells was demonstrated (B(max) [binding constant] of 5.19 +/- 0.70 x 10(-7) micromol of HDL bound/mg cell protein and K(b) of 2.83 +/- 0.22 nM). Tetranitromethane alters apo A-I, preventing binding to its cognate receptor. Tetranitromethane-modified HDL did not bind to mesangial cells and had no effect on [3H]thymidine incorporation. Addition of HDL to mesangial cells caused an immediate transient increase in free intracellular calcium in several representative mesangial cells, similar to the response seen with platelet-derived growth factor. The mitogenic effect of HDL was not altered after attenuation of cellular protein kinase C activity, but the stimulatory effect of HDL alone and in combination with insulin on DNA synthesis was completely eliminated after inhibition of cellular tyrosine kinases by 24-h pretreatment with 0.25 microM herbimycin A. Thus, HDL binds to a specific apo A-I-dependent receptor, promotes DNA synthesis, and initiates second-messenger events by a tyrosine kinase-dependent and protein kinase C-independent mechanism.
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PMID:HDL causes mesangial cell mitogenesis through a tyrosine kinase-dependent receptor mechanism. 925 51

The obese Zucker rat represents a model of obesity combined with insulin resistance and hyperlipidaemia, which over a period of several months develops spontaneous glomerulosclerosis. The present study addressed the question as to whether glomerular sclerosis was associated with alterations in the degradation of matrix components. In the early phase (up to 6 months) glomeruli from obese rats displayed increased total collagen content (+64%) and decreased gelatinolytic activity (-34%) as compared to lean control animals. This decline in glomerular gelatinolytic activity was due to a reduction in gelatinase B [matrix metalloproteinase (MMP)-9]. Glomerular MMP-9 mRNA was reduced 4.6 +/- 0.6-fold (n = 3; p < 0.05), MMP-9 protein was not detectable by Western blotting and MMP-9 activity was considerably suppressed in gelatin zymograms. MMP-2, in terms of mRNA expression and activity, was unchanged. Tissue inhibitor of metalloproteinases (TIMP)-1 mRNA expression, TIMP-1 protein (immunohistochemistry) and TIMP-1 activity (reverse zymography) were enhanced in glomeruli from obese rats, while TIMP-2 mRNA remained unchanged. Moreover, mRNA for the alpha 1 IV collagen chain was 2.1 +/- 0.8-fold higher in glomeruli isolated from obese animals (n = 3; p < 0.05). These findings indicate that matrix expansion in glomeruli from obese Zucker rats is due to both enhanced synthesis of matrix components as well as reduced degradation by matrix metalloproteinases. Apparently the latter effect is based on a reduction in MMP-9 and up-regulation of its inhibitor TIMP-1.
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PMID:Differential regulation of glomerular gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in obese Zucker rats. 930 Feb 40

Chronic rejection is a clinical syndrome characterized by a progressive decline in renal allograft function and nonspecific histologic findings of interstitial fibrosis, glomerulosclerosis, and fibrointimal proliferation of intrarenal arteries. Most late allograft failure that is not due to death with a functioning allograft is caused by chronic rejection. Although the pathogenesis and treatment of chronic rejection are unknown, a number of epidemiological studies have examined clinical correlates for possible clues to its pathogenesis. Clinical correlates for chronic renal allograft rejection can be classified in two broad categories: immune (alloantigen-dependent) and non-immune (alloantigen-independent). The strongest evidence that chronic rejection is immune mediated comes from its association with acute rejection and the degree of histocompatibility mismatching. However, not all acute rejection leads to chronic rejection, and there is little evidence that newer immunosuppression regimens which effectively prevent acute rejection have reduced the incidence and severity of chronic rejection. Therefore, many clinical investigators have also looked for potential non-immune causes of chronic rejection. Putative non-immune risk factors include donor source (living-related vs. cadaveric), cold ischemia time, delayed graft function, size mismatching, donor age, donor and recipient gender, recipient race, hyperlipidemia, and hypertension. Although there is little evidence supporting a cause and effect relationship between any immune or non-immune risk factor and chronic rejection, these clinical associations suggest a number of potentially important areas for further study.
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PMID:Clinical correlates to chronic renal allograft rejection. 940 26

Treatment modalities in severe nephrotic syndrome have to consider (a) the underlying glomerular diseases as well as (b) the extrarenal complications. Occasionally acute renal failure develops on the basis of an unknown nephrotic syndrome; if a primary glomerular disease is diagnosed by biopsy, immunosuppressive therapy is optional. In type I and type II diabetes development of a severe nephrotic syndrome is usually not reversible. To avoid the rapid decline of renal function a consequent antihypertensive therapy is the treatment of choice in this stage of the disease. Treatment of primary glomerular diseases with severe (NS) includes frequently relapsing minimal change nephropathy (MCN) that can be treated with prednisolone 1 mg/kg/day until remission occurs. For prolongation of the remission cyclophosphamide 2 mg/kg/day for eight weeks, or alternatively cyclosporine A 3 to 5 mg/kg/day for six months, can be given. In steroid-resistant focal segmental glomerulosclerosis (FSGS) eight weeks of treatment with cyclophosphamide 2.5 mg/kg/day or six months treatment with cyclosporine A 3 to 5 mg/kg/day can induce a partial or complete remission in up to 20% of the patients. In membranous glomerulopathy with severe NS, one month of therapy with prednisolone followed by chlorambucil for one month (all together 6 months) improves the renal outcome of the patients compared to controls. Alternatively, cyclophosphamide 2 mg/kg/day plus 30 mg prednisolone/day can be given for a couple of months. Extrarenal complications of a severe NS are: (a) edema; (b) thromboembolism; and (c) lipid abnormalities. If nephrotic patients are resistant to orally administered loop diuretics, they should be treated in addition intravenously with hydrochlorothiazide p.o. Nephrotic patients with a serum albumin level < 20 g/liter should be routinely anticoagulated. Extensive hyperlipidemia in severe NS can be treated with HMG-CoA reductase inhibitors.
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PMID:Treatment of severe nephrotic syndrome. 947 89

The association between hyperlipidemia and renal disease was noted by Virchow as early as the 19th century. Subsequently, similar histopathological lipid depositions were confirmed-in diverse human and experimental renal disease. Although, no studies have been established in man to suggest a causal relationship between lipids and the pathogenesis of renal disease, compelling evidence accumulated in experimental animals suggests a direct role of lipids in the initiation and progression of glomerular disease. These studies showed that cholesterol-feeding to various experimental animals induced the development of glomerular injury. Furthermore, the treatment of hyperlipidemic animals with lipid lowering drugs prevented the development of glomerulosclerosis. In this article, we will review recent advances made in understanding various aspects of lipid-mediated renal injury including biochemical mechanisms of hyperlipidemia, a possible direct role of hyperlipidemia in the pathogenesis of renal disease, pathobiological accumulation of lipids and lipoproteins, biochemical and histological similarities between systemic atherosclerosis and glomerulosclerosis, and cellular processes involved in the development of glomerular disease. Furthermore, we will define cellular and molecular hypotheses that provide putative mechanisms by which hyperlipidemia and atherogenic lipoproteins induce series of cytoregulatory peptide-mediated events involved in the development of glomerular disease.
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PMID:Hyperlipidemia and kidney disease: concepts derived from histopathology and cell biology of the glomerulus. 947 47

Despite the high rates of rejection, allograft failure, and patient death in the early years of renal transplantation, some patients have done remarkably well. Forty-three (17 living related donor and 26 cadaver donor recipients) such patients with an allograft that functioned for 19 years or more (range, 19 to 29 years) were followed up at this center. The patients included 24 men and 19 women, with a mean age at transplantation of 29 years, of whom 39 were white and four were black. At most recent follow-up, the mean daily dose of azathioprine was 104 mg (range, 50 to 175 mg) and that of prednisone was 10 mg (range, 5 to 20 mg). Mean serum creatinine level was 1.6 mg/dL (range, 0.7 to 5.4 mg/dL). Acute rejection occurred in 14 (33%) patients. Nine patients had one episode and five patients had two episodes of acute rejection. Long-term risks to the recipients appeared in the form of coronary artery disease in 10 (23%) patients; malignancy in 13 (30%) patients, which included nine patients with skin malignancy; and chronic hepatitis C virus (HCV) infection in four patients, two of whom died of complications of liver failure. Other complications included avascular bone necrosis in five patients, which required total hip replacement in two patients; hyperlipidemia requiring treatment in 16 (37%) patients; posttransplantation diabetes mellitus in 10 (23%) patients after a median of 17.5 years (range, 1 to 23 years); and hypertension in 23 (53%) patients. There were seven deaths (three of coronary artery disease, two of liver failure, one each of sepsis and malignancy) and eight graft losses (five to death with function, two to chronic rejection, and one to focal and segmental glomerulosclerosis). Although long-term allograft success results in patients receiving minimal amounts of immunosuppression and having good renal function, long-term renal transplant survivors are at risk for significant morbidity even in the third decade posttransplantation.
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PMID:Characteristics of long-term renal transplant survivors. 966 30

Although hyperlipidemia has been associated with the progression of glomerulosclerosis, little attention has been directed toward the use of lipid-lowering agents in altering diabetic nephropathy. We tested the hypothesis that lovastatin and the combination of lovastatin and enalapril would preserve renal function in streptozotocin-induced diabetic Wistar rats. Five groups of animals were studied: group 1, nondiabetic (n = 10); group 2, diabetic, insulin only (n = 12); group 3, lovastatin, (15 mg/kg/day, n = 13); group 4, enalapril, (50 mg/L drinking water, n = 10) and group 5, lovastatin plus enalapril, (n = 14). After 8 weeks of treatment, glomerular filtration rate (GFR, insulin clearance) was measured in anesthetized animals. The diabetic group was characterized by a GFR of 0.18 +/- 0.03 ml/min/g of kidney weight (gKW), a blood glucose level of 441 +/- 36 mg/dL, plasma cholesterol and triglyceride levels of 64 +/- 6.0 and 103 +/- 26.0 mg/dL. Lovastatin preserved GFR, 0.52 +/- 0.06 ml/min/gKW compared with the diabetic control subjects (P < 0.05). Enalapril also maintained GFR (0.42 +/- 0.06 ml/min/gKW, P < 0.05). In the lovastatin plus enalapril group, GFR (0.62 +/- 0.05 ml/min/gKW) was greater than in the enalapril group (P < 0.05), but was not different from the lovastatin group. Plasma lipid levels were not altered in any of the groups. Assessment of the kidneys by histology after treatment showed that the mesangial matrix injury score was better in the lovastatin, enalapril, and lovastatin plus enalapril groups compared with the diabetic group (P < 0.05). Lovastatin, enalapril, and lovastatin plus enalapril abrogated the decline in GFR and glomerular injury in diabetic rats. Lovastatin's direct renal protective effect seems to be independent of its lipid-lowering properties.
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PMID:Lovastatin preserves renal function in experimental diabetes. 1021 Mar 55

We report on a 22-year-old female with focal glomerular sclerosis and hyperlipidemia who did not respond to long-term steroid or immunosuppressant therapy. When low-density lipoprotein (LDL) apheresis was performed, her total daily protein excretion decreased, serum albumin increased, total cholesterol decreased from 1,052 mg/dl to 148 mg/dl after 3 months, and the serum lipoprotein(a) level also decreased from 117.8 mg/dl to 9.1 mg/dl. After this therapy, her clinical course was well maintained. By controlling hyperlipidemia, including oxidized low-density lipoprotein and lipoprotein(a), low-density lipoprotein apheresis may produce clinical improvement in focal glomerular sclerosis.
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PMID:Low-density lipoprotein apheresis for focal glomerular sclerosis. 1022 34

Nephropathy in patients with type I and II diabetes mellitus is a rapidly increasing problem worldwide. Studies using both glomerular and tubular cells have delineated some of the consequences induced by acute hyperglycemia. In vitro studies have clearly demonstrated that exposure of cultured renal cells, such as glomerular mesangial cells and proximal tubular epithelial cells, to elevated glucose concentrations, may alter cell proliferation and/or extracellular matrix turnover. The latter is effected both directly and indirectly by the alteration of cytokine generation. Furthermore, these in vitro studies have allowed detailed examination of the mechanisms by which exposure of these cells to high ambient glucose concentrations may alter cell function. Extension of these studies to the experimental in vivo situation has confirmed most of the in vitro findings. Important insights gained from models of type I diabetes (i.e. streptocotocin-induced diabetes) as well as type II diabetes (i.e. Goto-Kakizaki (GK) rats and obese Zucker rats) include: (1) The demonstration that increased glomerular cell proliferation and renal matrix accumulation, driven by TGF-beta and/or PDGF, occur in streptocotocin-induced diabetes, yet that nephropathy in these rats does not progress to renal failure. (2) The demonstration that prolonged mild type II diabetes does induce morphological changes characteristic of pre-clinical diabetic nephropathy in GK-rats but does not result in albuminuria or progressive renal disease. (3) The demonstration that the association of type II diabetes with hyperlipidemia in obese Zucker rats results in early podocyte damage and subsequent progression to glomerulosclerosis, tubulointerstitial damage, and renal insufficiency. Identification of the mediators involved in the above processes and in particular of the conditions that will determine progression of subclinical morphological changes to overt nephropathy and renal failure will likely result in future novel therapeutic approaches to diabetic nephropathy.
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PMID:Progression of diabetic nephropathy. Insights from cell culture studies and animal models. 1035 11

Hyperlipidemia is a well-recognized complication of the nephrotic syndrome and is a factor contributing to the progression of the initial glomerular injury and the development of glomerulosclerosis. Apolipoprotein E (apoE) is a plasma protein and apoE epsilon 4 allele is associated with higher plasma cholesterol levels. With this in mind, we studied apoE phenotypes and alleles in children with nephrotic glomerular diseases (NGD, n=29), including idiopathic nephrotic syndrome (n=16), membranoproliferative glomerulonephritis (n=7), and focal segmental glomerulosclerosis (FSGS, n=6). Children with NGD had a higher epsilon 4 allele frequency (20.7%) than controls (10.8%), and those with FSGS had both higher apoE4/3 (66.7%) and epsilon 4 allele (33.3%) frequencies than controls (20.4% and 10.8%, respectively). In IgA nephropathy (n=30, disease controls), no significant association with specific apoE was found. Further studies are needed to clarify the significance of the observed high frequencies of apoE epsilon 4 allele in children with NGD and apoE4/3 phenotype distribution in FSGS.
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PMID:Apolipoprotein E epsilon 4 allele and nephrotic glomerular diseases in children. 1035 12


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