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)

Diabetic nephropathy is preceded by 'hyperfiltration' mediated by dilatation of the afferent arterioles to the glomeruli by means of IGF-1, prostaglandins, bradykinin, nitric oxide and atrial natriuretic peptide, together with constriction of the efferent arterioles by local thromboxane A2. Raised glomerular intracapillary pressures might then contribute to glomerulosclerosis, but in any case there is permeability of the vascular endothelium. AGEPs and lipid peroxides can explain this. AGEPs, or simply intermittently high levels of glucose, also account for synthesis of extracellular matrix proteins that lead to thickening of the basement membrane and glomerulosclerosis. Another glucose product, glucosamine-6-phosphate, is formed when there is hexosamine flux along with insulin resistance in tissues, and is implicated in glomerulosclerosis, since it also stimulates TGF-beta transcription. In seeking to explain proteinuria, depletion of heparan sulphates from the endothelial cells and GBM is now established as a principal cause. In addition to a high glucose reducing the synthesis of heparan sulphates, it has now been shown that high glucose may depress the synthesis of heparin sulphate proteoglycan.
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PMID:How does hyperglycaemia predispose to diabetic nephropathy? 930 34

Heme oxygenase (HO) catalyzes degradation of heme to biliverdin, iron, and carbon monoxide. It consists of three isoforms: an inducible form (HO-1), a constitutive form (HO-2), and the third isoform (HO-3), with properties similar to HO-2. There is limited evidence to suggest that the induction of HO-1 may have anti-inflammatory effects in an in vivo model of oxidative stress-mediated renal injury. We experienced the first human case of HO-1 deficiency. The patient had persistent proteinuria and hematuria, with biochemical evidence of renal tubular injury. We obtained three consecutive renal specimens: two from renal biopsies at 2 and 5 years of age and the third from autopsy at 6 years of age. The patient had systemic vascular endothelial-cell injury with massive intravascular hemolysis. The serum was loaded with heme and a large amount of heme-conjugated haptoglobin. A high concentration of haptoglobin was also detectable in urine. Mesangial proliferation or change in glomerular capillary-wall thickness was relatively mild to moderate in all specimens. Electron microscopic examination showed widespread endothelial detachment and subendothelial deposits of an unidentifiable material. It was striking that tubulointerstitial injury, with tubular dilatation and/or atrophy, interstitial fibrosis, and inflammatory cell infiltration, advanced progressively. Tubular epithelial cells were injured, and massive deposition of iron and haptoglobin was detectable. Bowman's capsules were dilated significantly, probably secondary to the collapse of atrophic tubuli. This is the first report to show that HO-1 has critical roles in vivo in protecting renal tubuli, in addition to vascular endothelium, from oxidative injury.
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PMID:Tubular injury as a cardinal pathologic feature in human heme oxygenase-1 deficiency. 1079 20

An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since vascular endothelium is the site of formation of several substances, we have investigated the rate of progression of carotid atherosclerosis and the contribution of endothelin (ET-1), lipid peroxides [measured as thiobarbituric acid reacting species (TBARS)] and 6-keto-Prostaglandin-F1A (6-keto-PG-F1A) at baseline and after 30-months. Fifty patients with Type 2 diabetes without evidence of macroangiopathy, hypertension, proteinuria or proliferative retinopathy, and 27 healthy, non-diabetic persons were studied. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by b-mode ultrasound. The IMT values was significantly increased in diabetic subjects (at baseline: 1110 +/- 310 microm, after 30 months: 1260 +/- 280 microm, p < 0.01), but not in control subjects (1100 +/- 280 microm, 1200 +/- 290 microm, respectively). At baseline time both groups had similar levels of ET-1, TBARS and 6-keto-PG-F1A. In 30-months follow-up, the ET-1 level 8.0 pmol/l (5.8-10.7) was significantly elevated in diabetic subjects, compared with the level at baseline time 7.43 pmol/l (4.8-11.1) p < 0.01. No significant differences were found in the other examined parameters in the studied groups. Although insulin levels remained unchanged in the two studied groups, in 30 months follow-up, the insulin level in the diabetic subjects, 92.4 +/- 35.1 pmol/l was significantly elevated compared with those of control subjects 76.0 +/- 31.0 pmol/l, p < 0.05. In conclusion, endothelis is the main associate of the change of IMT value over 30 months in diabetic patients, in whom the extent of atherosclerosis was significantly greater than in control subjects.
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PMID:Progression of carotid atherosclerosis and the role of endothelin in diabetic patients. 1175 71

The role of the vascular endothelium in progressive renal disease is not well understood. This review presents evidence that progressive renal disease is characterized by a progressive loss of the microvasculature. The loss of the microvasculature correlates directly with the development of glomerular and tubulointerstitial scarring. The mechanism is mediated in part by a reduction in the endothelial proliferative response, and this impairment in capillary repair is mediated by alteration in the local expression of both angiogenic (vascular endothelial growth factor) and antiangiogenic (thrombospondin 1) factors in the kidney. The alteration in balance of angiogenic growth factors is mediated by both macrophage-associated cytokines (interleukin-1beta) and vasoactive mediators. Finally, there is intriguing evidence that stimulation of angiogenesis and/or capillary repair may stabilize renal function and slow progression and that this benefit occurs independently of effects on BP or proteinuria. Therefore, angiogenic agents may represent a novel therapeutic approach for slowing the progression of renal disease.
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PMID:Role of the microvascular endothelium in progressive renal disease. 1185 89

We review the mechanisms by which arterial hypertension induces target organs damage, particularly the heart, kidney, and vascular endothelium, which is manifested as ventricular hypertrophy, proteinuria, and renal failure and endothelial dysfunction. Furthermore, the effect of antihypertensive treatment in these situations is analyzed. Experimental and clinical studies show that angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonist drugs are more efficient than other antihypertensive treatments in the reversal of left ventricular hypertrophy and proteinuria, in delaying kidney damage and improving of endothelial function.
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PMID:[Impact of antihypertensive treatment on target organs]. 1200 72

Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme alpha-galactosidase A (alpha-Gal A). The lack of alpha-Gal A causes an intracellular accumulation of glycosphingolipids, mainly globotriaosyceramide (GL3). Affected organs include, among others, the vascular endothelium, heart, brain, and kidneys, leading to end-stage renal disease (ESRD). Since Fabry disease cannot be cured at present, clinical management is symptomatic. Enzyme replacement therapy (ERT) with recombinant alpha-Gal A has been introduced as a new therapeutic option for the treatment of Fabry patients. Short-term (one year) clinical studies have positively correlated ERT with improvement of clinical symptoms and microvascular endothelial cell clearance. Treatment outcome concerning severe organ manifestations such as proteinuria and renal function impairment, left ventricular hypertrophy, and heart failure in the long run has yet to be shown. In our studies we used sensitive and noninvasive techniques such as ultrasound-based strain rate imaging and magnetic resonance imaging (MRI), combined with MR-spectroscopy (MR-S), for the quantification of functional abnormalities at an early stage of the disease and during long-term follow-up. Future issues should determine the appropriate timing to start therapy and how children and heterozygous females should be managed. Given the diagnostic and therapeutic potential today, it is of importance to identify patients at an early stage and to start therapeutic intervention before progression of organ damage is inevitable.
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PMID:Fabry disease: diagnosis and treatment. 1269 40

The aim of the review is to discuss recent investigations on the glomerular filtration barrier. The barrier consists of three layers: the vascular endothelium, the glomerular basement membrane and the slit diaphragm located between podocyte foot processes. The main components of the slit diaphragm are nephrin, the product of NPHS1 gene and podocin, the product of NPHS2 gene. Mutations in NPHS1 lead to congenital nephrotic syndrome of the Finnish type (CNF), whereas NPHS2 mutations result in focal segmental glomerulosclerosis (FSGS). In both cases massive proteinuria is accompanied by the effacement of podocyte foot processess. Reduced expression and redistribution of nephrin and podocin are also seen in podocytes of patients with acquired glomerulopathies. The results suggest that those proteins play a pivotal role in the processes responsible for glomerular filtration. Together with podocin and CD2AP (CD2-associated protein), nephrin forms a complex determining the integrity of the slit diaphragm. Its function has not yet been fully understood and the pathways of signal transduction need to be elucidated.
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PMID:[Structure and function of the glomerular filtration barrier]. 1599 42

Preeclampsia affects 3-5% of pregnancies and can have a significant impact on health for both mother and fetus. Risk factors include maternal co-morbidities such as obesity and chronic hypertension, paternal factors, and genetic factors. New hypertension and proteinuria during the second half of pregnancy are key diagnostic criteria, but the clinical features and associated prognostic implications are somewhat heterogeneous and may reflect different mechanisms of disease. Renal dysfunction and proteinuria correspond to the pathologic finding of glomerular endotheliosis, and generally resolve after cure of preeclampsia through fetal and placenta delivery. The molecular mechanisms behind this disease are being discovered and refined. The initial etiologic agents are currently unknown. Pathologic studies show abnormal development of an ischemic placenta with a high-resistance vasculature, which cannot deliver an adequate blood supply to the fetoplacental unit. Endothelial dysfunction plays a central role in the pathogenesis of the maternal syndrome. Dysfunctional endothelial cells produce altered quantities of vasoactive mediators, which lead to a tip in the balance towards vasoconstriction. An imbalance in circulating angiogenic factors is emerging as a prominent mechanism that mediates the endothelial dysfunction and the clinical signs and symptoms of preeclampsia. Soluble fms-like tyrosine kinase 1 (sFlt1), an endogenous anti-angiogenic factor that is a potent vascular endothelial growth factor (VEGF) antagonist, is highly elevated in preeclampsia. VEGF is not only important in angiogenesis, but also in maintaining endothelial health including the formation of endothelial fenestrae (a hallmark of the glomerular vascular endothelium). sFlt1 overexpression in animals induces glomerular endotheliosis with the loss of endothelial fenestrae that resembles the renal histological lesions of preeclampsia. More severe forms of preeclampsia, including the HELLP syndrome, may be explained by a concomitant elevation in both sFlt1 and soluble endoglin, another anti-angiogenic factor. Unraveling of the molecular mechanisms behind preeclampsia may help to expand our armamentarium to treat patients in a more directed fashion, as current management consists of supportive care and expedited delivery. Finally, long-term outcomes of women with preeclampsia include a significantly increased risk for hypertension and cardiovascular disease, including mortality, which may warrant more aggressive screening and treatment in this population.
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PMID:Pre-eclampsia: clinical manifestations and molecular mechanisms. 1757 Sep 33

Anderson-Fabry disease (AFD) is a rare, X-linked lysosomal storage disease that leads to progressive intracellular accumulation of globotriaosylceramide in visceral organs and the vascular endothelium. We report two patients with end-stage renal disease who received renal allograft from deceased female donor who died from heart failure. A 62-year-old women received a renal allograft in July 2006. Except for low-range proteinuria, renal function was normal until 6 months after transplantation when serum creatinine increased from 120 to 150 micromol/L. A renal biopsy was performed. Based on the specific pathological finding, AFD in donor was suspected. In order to prove the diagnosis, the other recipient also underwent renal biopsy 3 months later. This was 45-year-old female with stable graft function and nonnephrotic proteinuria. Light microscopic findings included a 'foamy' appearance of affected cells with swelling and vacuolization of podocytes. Electron microscopic finding show mesangial cells and podocytes filled with dense lysosomal granules appearing as myelin figures and 'zebra bodies'. Changes were less intensive than in the biopsy of the first recipient. The donor was 54-year-old Italian women who died on the Adriatic coast after heart attack. This is the first case of AFD found in a kidney allograft from deceased donor.
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PMID:Anderson-Fabry disease in kidneys from deceased donor. 1794 59

Fabry disease is an X-linked lysosomal storage disorder which is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. The lack of enzyme causes a progressive intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (GL3). Affected organs are, among others, the vascular endothelium, heart, brain and kidneys, as well as the central and peripheral nervous system. With the approval of enzyme replacement therapy (ERT) in 2001, a specific treatment approach was opened for the first time. Randomized and placebo-controlled trials have shown the safety and efficacy of ERT with improvement of clinical symptoms and microvascular endothelial cell clearance. Long-term treatment outcomes in patients with severe organ manifestations, in particular proteinuria and renal function impairment, are still critical and warrant further investigation. Besides ERT being an optimized adjunctive therapy, timely initiation of ERT is important to assure optimal medical care. Subsequent follow-up assessments should be carried out in all patients on a regular basis to evaluate treatment outcomes.
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PMID:Update on Fabry disease: kidney involvement, renal progression and enzyme replacement therapy. 1826 34


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