Biomedical subjects

N S Nahman

Publications and source records attributed to N S Nahman.

At least 19 recordsLinked to original sources

PubMed2001

Renoprotection: one or many therapies?

BACKGROUND: Renal disease that progresses to end-stage renal disease (ESRD) imposes a great burden on the affected individual and on society, which mainly bears the cost of ESRD (currently more than $10 billion to treat about 333,000 patients annually in the U.S.). Thus, there is a great need to identify therapies that arrest the progression mechanisms common to all forms of renal disease. Progress is being made. Perhaps the most visible advance is the randomized controlled trials (RCT) demonstrating the renoprotective effects of angiotensin-converting enzyme (ACE) inhibitors. There are also numerous other promising renoprotective therapies. Unfortunately, testing each therapy in RCT is not feasible. Thus the nephrologist has two choices: restrict renoprotective therapy to those shown to be effective in RCT, or expand the use of renoprotective therapies to include those that, although unproven, are plausibly effective and prudent to use. The goal of this work is to provide the documentation needed for the nephrologist to choose between these strategies. METHODS: This work first describes the mechanisms believed to be involved in the progression of renal disease. Based largely on this information, 18 separate interventions that slow the progression are described. Each intervention is assigned a level of recommendation (Level 1 is the highest and Level 3 the lowest) according to the strength of evidence supporting its renoprotective efficacy. RESULTS: The number of interventions at each level of recommendation are: Level 1, N = 4; Level 2, N = 4; Level 3, N = 10. Our own experience with the multiple-risk-factor intervention is that most patients can achieve the majority of the Level 1 and 2 interventions, and many of the Level 3 interventions. We recommend the expanded renoprotection strategy. CONCLUSION: This work advances the hypothesis that, until better information becomes available, a broad-based, multiple-risk-factor intervention intended to slow the progression of renal disease can be justified in those with progressive nephropathies. This work is intended primarily for clinical nephrologists and thus each recommended intervention is described in substantial practical detail.

Disease Progression↗

PubMed2000

Microsphere-adenoviral complexes target and transduce the glomerulus in vivo.

BACKGROUND: Developing new treatments for glomerulonephritis makes the glomerulus a logical target for gene therapy. Microspheres may lodge in the glomerulus, and replication-deficient recombinant adenoviruses are potent mediators of gene transfer. We postulated that adenoviral-microsphere complexes could result in DNA transfer (transduction) into glomerular cells in vivo. METHODS: Two adenoviruses, each one containing a luciferase or beta-galactosidase (beta-gal) transgene expression cassette, were complexed to polystyrene microspheres. To assess in vivo glomerular transduction with this tool, male Sprague-Dawley rats underwent aortic injections with adenovirus linked to 11 or 16 microm diameter microspheres. RESULTS: After 48 hours, adenoviral-microsphere complexes resulted in transduction of up to 19% of glomeruli per kidney section. Endothelial and mesangial cells were transduced with this approach, and transprotein expression persisted for 21 days. Transduction efficiency was greater in the 16 microm group. For all rats, there was a strong correlation between kidney luciferase levels and the number of beta-gal-positive glomeruli (r = 0.87), indicating that transgene expression was primarily glomerular in location. This was supported by reverse transcriptase in situ polymerase chain reaction, which demonstrated glomerular localization of the beta-gal transgene. CONCLUSIONS: The aortic injection of adenoviral-microsphere complexes transduces the glomerulus in vivo and may be a useful tool in developing approaches to gene therapy of glomerular disease.

Adenoviridae↗

PubMed1999

Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy.

The benefit of angiotensin-converting enzyme (ACE) inhibitor (i) therapy in diabetic glomerulosclerosis is thought to be largely the result of attenuation of angiotensin II (AngII) effects on blood pressure, glomerular hemodynamics and hypertrophy, and tissue fibrosis. The present study was undertaken to determine whether the addition of AngII receptor antagonist therapy to ACEi therapy in diabetic nephropathy results in attenuation of AngII effects beyond that achieved by ACEi therapy alone. Seven patients were studied as inpatients on the General Clinical Research Center each for 3 consecutive weeks as follows: week 1, the patients' usual regimen which included daily oral moderate to high dose ACEi therapy; week 2, the patients' usual regimen plus oral losartan (an antagonist (a) of the angiotensin type 1 receptor, AT1) 50 mg (n = 3) or 100 mg (n = 4) daily; week 3, return to the patients' usual regimen. Diet, physical activity, and blood glucose were held as constant as possible during the three weeks of daily testing. We found that plasma renin levels increased significantly during combination therapy and then returned to baseline values with discontinuation of AT1a therapy: mean baseline renin values (week 1) 3.0 ng/ml/min +/- 1.1 SE, mean renin values during combination therapy (week 2) 7.0 ng/ml/min +/- 3.2 (p = 0.0078 by Wilcoxon rank sum test), mean renin values after discontinuation of AT1a therapy (week 3) 3.9 ng/ml/min +/- 2.0 (NS compared to baseline values). In addition, 2 patients developed transient hypotension when losartan therapy was initiated. During this short-term study, 24-hour proteinuria, serum creatinine, serum potassium, and plasma aldosterone were not changed significantly by combination therapy. We conclude that in patients with diabetic nephropathy addition of AT1a therapy to ACEi therapy attenuates AngII effects better than ACEi therapy alone. We suggest that combination therapy for the management of diabetic glomerulosclerosis merits further investigation.

Adult↗

PubMed1998

Successful DNA transfer in cultured human mesangial cells using replication deficient recombinant adenovirus.

BACKGROUND: Efficient transfer of DNA into human mesangial cells is an essential first step in the development of gene therapies for mesangial cell-mediated glomerulopathies. In the present studies, we assessed the ability of replication deficient recombinant adenovirus to transfer DNA (transduce) into primary cultures of human mesangial cells. METHODS: Primary cultures of human mesangial cells were transduced with an adenoviral vector (rAv beta-gal) containing a CMVllacZ promoter-reporter expression cassette coding for beta-galactosidase (beta-gal). We assessed soluble and histologic beta-gal activity, morphology, and phenotypic expression of mesangial cell transductants, durability of transduced mesangial cells by measuring transgene expression following trypsinization or after prolonged periods in culture and metabolic stability following transduction (as assessed by fibronectin biosynthesis). RESULTS: We showed that rAv beta-gal efficiently transduced mesangial cells in a dose-dependent fashion at a multiplicity of infectious units (MOI) ranging from 1 to 400 plaque forming units/cell (pfu/cell). One hundred percent of mesangial cells were transduced at an MOI of 100 pfu/cell. By electron microscopic evaluation, viral particles of approximately 85-90 nm were demonstrated in the cytoplasm of transduced cells. Following transduction, legal levels rose rapidly and were 10-fold greater than baseline levels after 2 hours. Beta-gal levels continued to rise for 7 days following transduction. Transduction with rAv beta-gal was well tolerated; mesangial cell transductants maintained normal morphology and phenotype, tolerated 3 cycles of trypsinization and maintained normal constitutive production of fibronectin. CONCLUSIONS: Gene transfer with adenovirus is an effective, well tolerated approach for introducing DNA into primary cultures of human mesangial cells.

Adenoviridae↗

PubMed1997

Renal artery dissection causing renal infarction in otherwise healthy men.

Arterial dissection is usually associated with pathological states such as malignant hypertension, severe atherosclerosis, severe trauma, Marfan syndrome, or Ehlers-Danlos syndrome. However, we report three cases in which renal artery dissection occurred in otherwise healthy, normotensive men. In two cases, the onset of symptoms of renal artery dissection was coincident with an unusual degree of physical activity. In the third case, the symptoms occurred while the patient was sitting but during a stressful business meeting. In each case, the patient experienced severe unilateral flank pain. Urolithiasis was suspected, but intravenous pyelography showed only ipsilateral impaired renal cortical perfusion, and the urinalyses showed no hematuria. The diagnosis of renal artery dissection was established by arteriography in two cases and by nephrectomy in one case. The latter case showed fibromuscular dysplasia by arteriography performed after the nephrectomy. The other two cases showed no evidence of fibromuscular dysplasia. We conclude that spontaneous renal artery dissection can occur in otherwise healthy individuals. Our experience and the reports of others indicate that this condition occurs mainly in men, conservative (nonsurgical) management is generally indicated, and the long-term prognosis is generally excellent. In some patients, an unusual degree of physical exertion might be the cause of renal artery dissection.

Adult↗

PubMed1997

Subacute bacterial endocarditis masquerading as type III essential mixed cryoglobulinemia.

An adult man presented severely ill with vasculitis of his lower extremities and with impaired kidney function. After detailed evaluation at a local hospital, a diagnosis of essential type III cryoglobulinemia was made. High-dose steroid and cyclophosphamide therapy was begun. The patient improved dramatically. However, 6 wk later when his steroid dose was reduced to 30 mg daily, vasculitis recurred. Intensifying his immunosuppressive therapy only worsened his condition. He was than transferred to the Ohio State University Medical Center for consideration for plasmapheresis for the presumed essential type III cryoglobulinemia. However, our evaluation showed that he had bacterial endocarditis causing his type III cryoglobulinemia. When immunosuppressive drugs were stopped and antibiotics were begun, his condition resolved completely. This case illustrates the difficulty of identifying infectious causes of cryoglobulinemia and emphasizes that an initial, highly favorable response of vasculitis to immunosuppressive therapy does not exclude an infectious cause for the vasculitis.

Acute Kidney Injury↗

PubMed1996

Angiotensin II induction of fibronectin biosynthesis in cultured human mesangial cells: association with CREB transcription factor activation.

We assessed the effect of angiotensin II on fibronectin biosynthesis a nd transcription factor activation in adult human mesangial cells in culture. We found that 10(-5) mol/L angiotensin II tended to increase fibronectin mRNA expression within 1 hour (1.2-fold +/- 0.3-fold of that in controls), with a significant increase after 4 hours (0.3-fold +/- 0.1-fold of that in controls, p < 0.05) and 24 hours (1.9-fold +/- 0.3-fold of that in controls, p < 0.02). In conjunction with increased fibronectin mRNA levels, angiotensin II exposure resulted in a significant elevation in immunoreactive fibronectin concentrations and the incorporation of (35S)-labeled methionine into fibronectin after 2 hours (224% +/- 23% of controls, p < 0.05). Angiotensin II also induced mesangial cell activation of the cyclic adenosine monophosphate response element binding protein (CREB) transcription factor, a DNA binding protein known to recognize specific regulatory elements present on the fibronectin gene promoter. Using the electrophoretic mobility shift assay, we showed that angiotensin II increased mesangial cell expression of the activated form of CREB after 4 hours (1.2-fold +/- 0.04-fold of that in controls, p < 0.05). To determine the importance of the CREB regulatory elements in mediating angiotensin II induction of fibronectin gene transcription, JEG-3 cells were transfected with plasmids containing fibronectin promoter-chloramphenicol acetyltransferase (CAT) reporter gene constructs with (FN510) or without (FN122) the CREB regulatory motifs. Angiotensin II resulted in a significant increase in CAT activity in FN510 transfectants (1.6-fold +/- 0.2-fold of that in controls, p < 0.05), but there was no effect of angiotensin II on FN122 transfected cells. These data demonstrate that angiotensin II stimulates fibronectin biosynthesis in adult human mesangial cells and suggest that the process may be regulated at the transcriptional level.

Angiotensin II↗

PubMed1996

Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. The Collaborative Study Group.

We designed a prospective, double-blind controlled trial to determine predictors of loss of renal function in patients with insulin dependent diabetes and established nephropathy. A total of 409 insulin-dependent diabetic patients with established nephropathy enrolled in a trial on the effect of Captopril on the rate of progression of renal disease. Baseline demographic, clinical (history and physical) and laboratory parameters were analyzed as risk factors for time to progression. Dichotomous characteristics were compared by Fisher's exact test and continuous characteristics with the Wilcoxon rank-sum test. Univariate proportional hazards regression analysis was used to estimate relative risk of nephropathy progression, and bivariate proportional hazard regression to identify interactions with the treatment group assignment. Multivariate proportional hazard regression was employed to determine which characteristics were independent risk factors. We found that a number of demographic and clinical characteristics were significantly associated with nephropathy progression even after adjustment for treatment group. However, after multivariate analysis, the risk factors that independently predicted progression were onset of IDDM later in life, parental diagnosis of IDDM, the presence of edema, increased mean arterial pressure, and an abnormal electrocardiogram. Likewise, a number of laboratory characteristics were also predictive of nephropathy progression. A low hematocrit, high blood sugar, and higher protein excretion predicted nephropathy progression as did a higher serum creatinine, particularly in the face of a normal serum albumin. In conclusion, this study identifies a number of clinical and laboratory risk factors that can predict which patients with insulin-dependent diabetes with established nephropathy are more likely to sustain a clinically important decrease in renal function over a median follow-up of three years.

Adolescent↗

PubMed1996

Copper-related blood indexes in kidney dialysis patients.

Previous work has suggested that kidney hemodialysis patients could be at risk for either moderate copper deficiency or copper toxicity. The present study examined copper-related blood indexes in subjects undergoing hemodialysis treatments with membranes that are not copper-based, in subjects undergoing chronic ambulatory peritoneal dialysis (CAPD), and in control subjects. Both dialysis groups had low plasma copper and ceruloplasmin activities. This occurred despite high plasma interleukin 6 concentrations, a situation that usually elevates plasma ceruloplasmin and copper values. CAPD and hemodialysis subjects had low ratios of ceruloplasmin activity to immunoreactive protein, and low ratios of plasma copper to ceruloplasmin protein. Both are signs of copper deficiency. In contrast, copper-containing erythrocyte superoxide dismutase (SOD) activities were high in hemodialysis subjects and showed a nonsignificant trend toward high values in CAPD subjects. Blood mononuclear cell copper contents were highly variable within each group, and there were no significant differences between groups. In conclusion, ceruloplasmin-related indexes in kidney dialysis patients not dialyzed with copper-based membranes suggested a tendency toward moderate copper deficiency. However, this contention could not be confirmed by erythrocyte SOD activity or mononuclear cell copper measurements.

Adult↗

PubMed1996

Nocturnal blood pressure in treated hypertensive African Americans Compared to treated hypertensive European Americans.

Previous studies have shown that African Americans (blacks) tend to have higher nocturnal blood pressure than European Americans (whites). The study presented here was undertaken to determine whether treatment of hypertension influences nocturnal blood pressure differently in blacks than in whites. To answer this question, this study measured nocturnal blood pressure by ambulatory blood pressure monitoring (ABPM) in treated hypertensive blacks and whites whose daytime blood pressures were comparable. Inclusion criteria for this study were: diagnosis of essential hypertension, absence of renal failure, and documentation of antihypertensive therapy, diabetic status, proteinuria status, and body weight. All of the black patients in our programs who underwent ABPM and met the above criteria were included in this study. White patients were included on the basis of having the same inclusion criteria as blacks and showing, by ABPM, daytime mean arterial pressure (MAP) in the same range as that of the blacks selected for this study. The results of nocturnal blood pressure were unknown to the investigators when the patients were selected for this study. In the blacks (N = 62) and whites (N = 72) selected for study, the mean daytime (0600 to 2200 h) MAP was 107 +/- 1 SE mm Hg for both the black and white cohorts. To assess nocturnal blood pressure, the period from 0100 to 0500 h was chosen because it likely encompassed an interval of sleep, which is associated with the nadir of nocturnal blood pressure. This interval was termed 0100 to 0500 h, "middle night." Mean middle night MAP was 97 +/- 12 mm Hg in blacks versus 90 +/- 14 mm Hg in whites (P < 0.006, unpaired t test). The greater middle night MAP in blacks compared with whites was a result of the higher diastolic pressure in blacks (80 +/- 11 mm Hg) versus whites (75 +/- 11 mm Hg) (P = 0.003). Mean middle night systolic blood pressure was numerically higher in blacks than whites (131 +/- 18 mm Hg versus 128 +/- 17 mm Hg), but this difference did not achieve statistical significance. The higher middle night blood pressure in blacks versus whites could not be explained by differences between the groups in daytime MAP, age, gender, body weight, serum creatinine level, proteinuria, diabetic status, or greater use of short-acting antihypertensive agents in blacks versus whites. It was concluded that when treated hypertensive blacks and whites are matched for the same daytime blood pressure, blacks tend to have significantly higher nocturnal blood pressure than whites. The magnitude of this difference suggests that it could contribute importantly to the greater target-organ damage that is seen in hypertensive blacks compared with hypertensive whites.

Antihypertensive Agents↗

PubMed1995

Cyclic adenosine monophosphate and protein kinase C modulate fibronectin production in cultured human mesangial cells.

To identify potential intracellular mediators of mesangial cell fibronectin production, we examined the effect of cyclic adenosine monophosphate and protein kinase C on fibronectin biosynthesis in cultured human mesangial cells. We found that increasing intracellular cyclic adenosine monophosphate resulted in a 2.6-fold increase in fibronectin mRNA expression within 15 minutes; this reached a plateau after 1 hour and fell below control levels by 24 hours. Cyclic adenosine monophosphate significantly increased both immunoreactive fibronectin levels and the incorporation of [35S]-labeled methionine into fibronectin after 1 and 2 hours (251% +/- 3% and 157% +/- 18% of controls, respectively). The induction of protein kinase C with phorbol ester also increased fibronectin mRNA expression. The effect was time and dose dependent. Phorbol ester significantly increased both immunoreactive fibronectin levels and the incorporation of [35S]-labeled methionine after 1 and 2 hours (174% +/- 2% and 224% +/- 6% of controls, respectively). Inhibition of protein kinase C with calphostin C attenuated constitutive and phorbol ester induced fibronectin biosynthesis. These studies indicate that cyclic adenosine monophosphate and protein kinase C regulate mesangial cell fibronectin biosynthesis and that protein kinase C may contribute to control of constitutive fibronectin production.

Cells, Cultured↗

PubMed1994

Renal artery pressure gradients in patients with angiographic evidence of atherosclerotic renal artery stenosis.

From October 1979 to August 1991, 231 patients underwent renal artery balloon angioplasty at The Ohio State University Hospitals. Atherosclerotic renal vascular disease was present in 171 of these patients. From this cohort, 138 patients undergoing their first angioplasty had renal artery pressure gradients performed before and after renal artery angioplasty. The demographics of this group included age 66.9 +/- 10 years (+/- SD), male 51%, white 94%, black 6%, diabetes mellitus 28%, systolic blood pressure 157 +/- 26 mm Hg, diastolic blood pressure 86 +/- 13 mm Hg, standard daily doses of antihypertensive medications 4.2 +/- 3, and serum creatinine 2.6 +/- 2.3 mg/dL. Plasma renin activity was measured in 25 patients and was shown to be elevated in 16. The renal artery stenoses were main renal artery 75%, orificial 22%, distal renal artery 1.4%, and combinations of the above 2.2%. Solitary kidneys were present in six patients (4.3%). Bilateral renal artery stenosis was present in 45% of patients and bilateral angioplasties were performed in one third of these patients. The preangioplasty systolic blood pressure gradient was 109 +/- 50 mm Hg (range, 20 to 230 mm Hg) and the postangioplasty renal artery pressure gradient was 12 +/- 16 mm Hg (range, 0 to 78 mm Hg) (P < 0.001). There were no complications related to measurement of the pressure gradients. The magnitude of the renal artery pressure gradients did not correlate with blood pressure level, number of antihypertensive medications, or serum creatinine level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Angiotensin-converting enzyme inhibition partially prevents diabetic organomegaly.

The present study was conducted to evaluate whether captopril prevents the organomegaly and accumulation of matrix proteins that normally accompanies the diabetic state. The following groups of rats were studied: normal rats, normal rats treated with captopril (30 mg/kg/d orally), streptozotocin diabetic rats, and diabetic rats treated with captopril. All rats were killed at 10 weeks for histologic and morphometric evaluation of tissues. Compared with the normal rats, the diabetic rats demonstrated significant hepatomegaly, nephromegaly, and cardiomegaly, and the increase in organ size was directly related to increasing levels of protein glycosylation. The development of organomegaly was partially prevented by captopril. We determined by morphometry that the hepatomegaly seen in the diabetic rats was due to an increase in cell size and number, while the nephromegaly seen in the diabetic rats was due to an increase in tubular and glomerular cell size and is associated with glomerular hypertrophy. Captopril prevented the development of hepatic and renal cell hypertrophy and glomerular hypertrophy. These effects of captopril were not associated with detectable changes in body weight or levels of glucose, protein glycosylation, glycosuria, or renal histologic changes secondary to glycosuria. The diabetic rats demonstrated significant glomerular mesangial matrix expansion, and captopril treatment partially prevented that expansion. In conclusion, captopril prevents, in part, the development of organomegaly in diabetic rats, and this effect is due mainly to the prevention of the development of cellular hypertrophy. The present findings are most consistent with a direct effect of captopril on cell metabolism during diabetes mellitus.

Analysis of Variance↗

PubMed1992

Effects of high glucose on cellular proliferation and fibronectin production by cultured human mesangial cells.

Diabetic glomerulosclerosis is characterized by the accumulation of the matrix protein fibronectin in the glomerular mesangium and could result from increased mesangial cell fibronectin synthesis induced by hyperglycemia. To test this hypothesis, we cultured human mesangial cells for up to 14 days in media containing normal (5 mM) or high glucose (20 to 115 mM) concentrations and assessed cellular proliferation and fibronectin synthesis. When compared to 5 mM glucose, high glucose levels significantly inhibited cellular proliferation in a dose dependent fashion, as assessed by direct cell counting and thymidine incorporation. After eight days in culture, tissue culture supernatant fibronectin levels, as assessed by ELISA, were significantly higher from cells cultured under high glucose conditions than cells exposed to normal glucose levels. After 14 days and when compared to 5 mM glucose, matrix fibronectin levels and fibronectin mRNA expression (by Northern analysis) were also increased by 20 mM glucose. To control for the osmotic effects of high glucose, mesangial cells were also cultured in the presence of 20 mM or 50 mM mannitol. Mannitol had no effect on cellular proliferation but significantly increased tissue culture supernatant fibronectin levels and fibronectin gene expression. These studies demonstrate that, in vitro, high glucose suppresses human mesangial cell proliferation and stimulates fibronectin synthesis. The increase in fibronectin synthesis may in part result from changes in osmolality induced by high glucose. These data suggest that increased mesangial cell fibronectin synthesis may play a role in the accumulation of glomerular fibronectin common to diabetic glomerulosclerosis.

Cell Division↗

PubMed1992

Modification of the percutaneous approach to peritoneal dialysis catheter placement under peritoneoscopic visualization: clinical results in 78 patients.

The placement of percutaneous peritoneal dialysis catheters under direct peritoneoscopic visualization is a relatively new technique for establishing peritoneal dialysis access. In this study, in which a modification of the Seldinger technique was used to facilitate the placement of the peritoneoscope, the experience with 82 consecutive catheterization procedures in 78 patients is reported. In 2 (2.4%) of 82 catheterization procedures, we were unable to enter the peritoneal cavity but experienced no other complications unique to the percutaneous approach. Of the 80 successful catheterization procedures, 76 represented first-time catheter placement and constituted a population subjected to life-table analysis examining catheter survival rates, the time to first cutaneous exit site or s.c. tunnel infection, and the time to first episode of peritonitis. After a follow-up period of 50.1 patient yr, 11 catheters were lost because of catheter dysfunction. Other clinical complications included peritoneal fluid leaks at the cutaneous exit site in 11 instances (0.22/patient yr), cutaneous exit site infection in 7 instances (0.14/patient yr), s.c. tunnel infection in 2 instances (0.04/patient yr), and 34 episodes of peritonitis (0.68/patient yr). The results of this study demonstrate that the suggested modification of the percutaneous placement of peritoneal dialysis catheters, under peritoneoscopic visualization, is a viable method for establishing peritoneal access.

Adult↗

PubMed1990

Continuous arteriovenous hemofiltration.

CAVH is a bedside form of dialysis that is used in the treatment of fluid and electrolyte disorders seen in critically ill patients. The major advantages of the procedure include (1) gradual, continuous therapy, which is ideal in hemodynamically unstable patients; (2) control of fluid balance; and (3) ease of administration in the ICU. The major disadvantages of CAVH include (1) a requirement for arterial access, (2) the need for anticoagulation, (3) the risks of infection from long-term indwelling vascular lines, and (4) the potential for significant volume depletion. The effectiveness of CAVH may continue to improve owing to technical developments in filter composition and the application of clinical tactics such as suction-assisted filtration, predilution fluid replacement, or regional heparinization. The next step in bedside dialysis is represented by CAVHD, which offers all of the advantages of CAVH as well as improved urea clearance.

Anticoagulants↗

PubMed1990

Cellular receptors for matrix proteins in normal human kidney and human mesangial cells.

In the present study we evaluated the distribution of cell adhesion molecules, referred as very late antigens (VLA), in the normal human kidney and in mesangial cells in culture (MC). In addition, we assessed the functional properties of VLA proteins on MC. Normal human kidney and MC were stained by immunoperoxidase with mouse monoclonal antibodies to VLA proteins. We demonstrated that VLA-3, a protein that binds FN, laminin and collagen, is the predominant VLA protein in the human glomerulus and on MC. VLA-3 is located in the mesangium and on the glomerular visceral epithelial cell and endothelial cell surfaces in contact with the glomerular basement membrane. VLA-1 was demonstrated in the glomerular mesangium and VLA-5, an FN specific receptor, was present in the mesangium on glomerular endothelial cells and on MC. VLA-2 and VLA-4 were not present in the normal glomerulus nor on MC. In functional studies we evaluated the binding of MC to FN coated surfaces and the binding and phagocytosis of FN coated fluorescent beads by MC. We showed that MC bind to FN coated surfaces and that the binding is inhibited by anti-FN antibodies, EDTA and peptides containing the amino acid sequence Arg-Gly-Asp (RGD). In addition, anti-VLA-5 but not anti-VLA-3 antibodies inhibited significantly the binding of MC to FN, MC demonstrated binding and phagocytosis of FN coated beads and, purified FN inhibited both phenomena. By affinity chromatography and immunoprecipitation we demonstrated that MC FN binding proteins and MC VLA proteins are composed of two distinct protein chains that have Mr characteristics similar to those of normal human fibroblasts VLA proteins. In conclusion, the glomerular distribution of VLA-3 suggests that this protein is primarily involved on the adhesion of glomerular cells to basement membranes and matrix. MC FN receptors (VLA-5) mediate the binding of MC to FN and could mediate the phagocytosis of FN coated antigen or immune complexes by mesangial cells.

Binding Sites↗

PubMed1990

The effects of ciclosporin in experimental glomerulosclerosis.

The acute and chronic effects of daily, oral ciclosporin (CS) therapy (25 mg/kg) on proteinuria, blood pressure, renal function and histology were studied in rats subjected to unilateral nephrectomy and 3 weekly intraperitoneal injections of the aminonucleoside of puromycin (PAN). PAN therapy resulted in heavy proteinuria by week 4 which declined by weeks 8 and 16. When CS therapy was started weeks after the last dose of PAN, acute, transient reductions in proteinuria and reversible rises in blood urea nitrogen (BUN) were observed. When CS or oil therapy was started with PAN and continued for 8 or 16 weeks, there were no differences in proteinuria; however, after 16 weeks, CS treated rats had significantly higher BUN levels [65 +/- 11 (23.2 +/- 3.9) vs. 41 +/- 5 mg/dl (14.6 +/- 1.8 mmol/l); p = 0.001], a higher percentage of sclerotic glomeruli (47 +/- 7 vs. 28 +/- 10%; p less than 0.0001) and extensive interstitial fibrosis. There was a strong correlation between glomerulosclerosis and extent of interstitial fibrosis (r = 0.951; p less than 0.0001). These studies demonstrate that rats with experimental focal glomerulosclerosis treated with CS show an acute, transient reduction in proteinuria; however, chronic (for 16 weeks) CS therapy significantly increases azotemia and results in an increase in glomerulosclerosis and interstitial fibrosis.

Animals↗