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Biomedical subjects

S Klahr

Publications and source records attributed to S Klahr.

At least 37 records · Page 2Linked to original sources
PubMed1998

Differential effects of ACE and AT1 receptor inhibition on chemoattractant and adhesion molecule synthesis.

Ureteral obstruction causes infiltration of the kidney by monocytes/macrophages. This infiltrate is significantly reduced by administration of an angiotensin-converting enzyme (ACE) inhibitor but not by a specific angiotensin II type 1 receptor (AT1 receptor) antagonist. Chemoattractants and cell surface adhesive molecules mediate monocyte/macrophage infiltration. Rats with unilateral ureteral obstruction (UUO) of 1, 3, or 5 days duration were untreated or given enalapril or SC-51316 in the drinking water. We measured the mRNA levels of monocyte chemoatactic peptide 1 (MCP-1), a chemoattractant, and levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), two cell surface adhesion proteins. MCP-1 mRNA increased significantly after 1 day of UUO and increased further through 5 days of UUO in the obstructed kidney. ICAM-1 mRNA also increased significantly after 1 day but steadily declined through 5 days of UUO in the obstructed kidney. VCAM-1 mRNA did not increase significantly until after 3 days of UUO and increased further through 5 days of obstruction. Enalapril or SC-51316 treatment had no significant effect on ICAM-1 mRNA levels. MCP-1 mRNA levels were reduced but remained significantly elevated. Enalapril significantly blunted the increase in VCAM-1 mRNA levels and VCAM-1 protein determined by immunocytochemistry; SC-51316 had no significant effect. Thus changes in VCAM-1 levels may account for the differential effect of enalapril and SC-51316 on monocyte/macrophage infiltration of the kidney during ureteral obstruction.

Angiotensin Receptor Antagonists↗
PubMed1998

Osteopontin expression in the kidney during unilateral ureteral obstruction.

Osteopontin is a bone protein also expressed in other tissues. Increased osteopontin is thought to be associated with tissue inflammation. We used immunocytochemical analyses and polymerase chain reaction amplification of mRNA to examine osteopontin expression and regulation in unilateral ureteral obstruction (UUO) in rats, a model of inflammatory kidney disease. In the obstructed kidney, osteopontin mRNA and protein were significantly increased. The increase reached 4-fold after 1 day of UUO and persisted at this level for the 5-day duration of UUO. Immunocytochemical analyses showed increased osteopontin protein in tubular cells of the obstructed kidney cortex from days 1 through 5 of UUO. No such significant increase was apparent in the glomerulus or interstitium. Increased osteopontin mRNA and protein likewise occurred in the tubular cells of the obstructed kidney of rats that had undergone whole-body irradiation to eliminate macrophage infiltration into the experimental kidney. Purified osteopontin was found to be a chemoattractant for macrophages isolated from the rat peritoneum. Enalapril treatment, which decreases macrophage infiltration of the obstructed kidney, had no effect on the increase in osteopontin mRNA but significantly attenuated the increase in protein in tubular cells. Western blot analysis of whole cortical homogenates revealed that the osteopontin antibody recognized one protein of 67 kD. The amount of this protein was substantially decreased in kidney homogenates obtained from enalapril-treated compared to untreated animals. Increased osteopontin synthesis may, therefore, contribute in part to the inflammatory response that characterizes obstructive nephropathy.

Animals↗
PubMed1998

Mechanisms of interstitial fibrosis in obstructive nephropathy.

Numerous pathological processes are involved in the renal tubulointerstitial fibrogenic reaction that occurs after ureteral ligation. Central to these maladaptive events is a florid interstitial monocytic infiltration of the tubulointerstitium, which is preceded by a proximal tubular up-regulation of macrophage chemoattractants. Once within the peritubular and periglomerular space, these macrophages are capable of releasing a potent armamentarium of peptide growth factors. TGF-beta has been singled out as a pivotal growth factor mediating fibrogenesis owing to its multifaceted effects on fibroblasts, tubular cells, matrix metalloproteinases, and TIMPs. A growing body of experimental studies using the rat hydronephrosis model is now demonstrating that angiotensin II may, in addition to its well-known hemodynamic effect, also be pro-inflammatory and pro-fibrogenic.

Angiotensin Receptor Antagonists↗
PubMed1998

Transcription factor NF-kappaB regulation of renal fibrosis during ureteral obstruction.

Irrespective of the etiology, many kidney diseases result in inflammation and fibrosis of the tubulointerstitium, with the subsequent loss of renal function. To initiate any disease process or for any disease process to progress, there must be changes in the transcription of genes within the affected tissue. The nuclear factor-kappa B (NF-kappaB) family of transcription factors regulates genes involved in inflammation, cell proliferation, and cell differentiation. This review discusses the NF-kappaB transcription factor family in general and the association of NF-kappaB activation with cellular/molecular events of renal inflammation and fibrosis.

Animals↗
PubMed1998

The role of growth factors, cytokines, and vasoactive compounds in obstructive nephropathy.

Renal interstitial inflammation and fibrosis occurs after ureteral obstruction. Fibrosis most likely develops as a consequence of an imbalance between extracellular matrix synthesis and deposition and the degradation and removal of matrix. Angiotensin II is rapidly stimulated after the onset of ureteral obstruction. Angiotensin II in turn upregulates other factors (transforming growth factor beta, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants). Blockade of angiotensin II synthesis or inability of this peptide to bind to its receptor lessened the increased levels of mRNA for TGF-beta and collagen IV. Increased levels of angiotensin II have a major role in the development of tubulointerstitial fibrosis after ureteral obstruction.

Angiotensin II↗
PubMed1998

Therapeutic approaches in obstructive uropathy.

Therapy for obstructive uropathy is largely determined by whether the obstruction involves one or both kidneys, and by the age of the patient. In the infant and child, obstructive uropathy is almost always due to a congenital malformation of the ureter, bladder, or urethra. Ultrasonographic prenatal diagnosis has permitted early detection and even fetal intervention for posterior urethral valves, although this form of treatment must be considered experimental at present. More important to the affected infant than optimal renal development is the prevention of pulmonary hypoplasia, which is a consequence of fetal oliguria and oligohydramnios. Congenital ureteropelvic junction (UPJ) obstruction is generally unilateral, and although there is controversy regarding the timing of surgical correction, current evidence favors early pyeloplasty. In the adult, obstructive nephropathy is often acquired, with ureteral obstruction usually a consequence of nephrolithiasis. Removal of the stone can be accomplished surgically or by lithotripsy. Bladder outlet obstruction is usually secondary to prostatic hyperplasia, which may progress slowly, allowing a delay in surgical intervention. Neurogenic bladder may require intermittent catheterization or cholinergic therapy; those with hypertonic bladder may benefit from anticholinergics. Regardless of the patient's age, prompt and accurate diagnosis is essential to planning an optimal strategy for the management of obstructive uropathy.

Animals↗
PubMed1998

Effect of a ketoacid-aminoacid-supplemented very low protein diet on the progression of advanced renal disease: a reanalysis of the MDRD feasibility study.

BACKGROUND: We reanalyzed the data of the Modification of Diet in Renal Disease (MDRD) feasibility study to ascertain the effects of ketoacid- and aminoacid-supplemented very low protein diets. METHODS: Sixty-six patients with advanced renal disease (Study B, baseline glomerular filtration rate (GFR) 7.5-24 ml/min/1.73 m2) were randomly assigned to a low protein diet (L, 0.575 g/kg/d), or a very low protein diet (0.28 g/kg/d) supplemented either with a ketoacid-aminoacid mixture (diet K) or with a mixture of essential aminoacids (diet J). Thirty patients with moderate renal disease (Study A, baseline GFR 25-80 ml/min/1.73 m2) were randomly assigned to a usual protein diet (M, 1.2 g/kg/d), diet L, or diet K. Mean follow-up was 14 months. RESULTS: In Study B, GFR decline differed among the three diets (p = 0.028). Pairwise comparisons showed that the mean +/- SE GFR decline in ml/min/mo in diet K [-0.250+/-0.072] was slower than in diet J [-0.533+/-0.074] (p = 0.008) despite similar achieved protein intakes. The mean GFR decline in diet L [-0.394+/-0.068] was intermediate between, and did not differ significantly from the rates of decline in the other two groups. In Study A, consistent with a hemodynamic effect, the mean GFR decline varied directly with the reduction in protein intake in diets M, L and K (p = 0.028) during the first four months of follow-up, but thereafter did not differ among the diet groups (p = 0.76). CONCLUSION: The study suggests that supplementation of a very low protein diet with the ketoacid-aminoacid mixture used in this feasibility study slowed the progression of advanced renal disease more than supplementation with an amino acid mixture.

Adult↗
PubMed1997

Rapid communication. Enalapril decreases nuclear factor kappa B activation in the kidney with ureteral obstruction.

The transcription factor nuclear factor kappa B (NF-kappa B) controls a number of genes associated with tissue inflammation and has been shown to be activated in the kidney with ureteral obstruction. In this investigation, we further explored NF-kappa B activation in the kidney cortex of rats with unilateral ureteral obstruction. Electrophoretic mobility shift assays combined with antibody supershift/depletion demonstrated that NF-kappa B subunits p50, p52, c-rel, p65 (RelA) and RelB were all activated. Immunocytochemical analysis using an antibody to the p50 subunit demonstrated activation occurring predominantly in nuclei of tubular cells. Treatment of animals with unilateral ureteral obstruction with an oral ACE inhibitor significantly decreased NF-kappa B activation. This suggests that the antiinflammatory effect of ACE inhibitors in renal disease is in part due to a blunting of NF-kappa B activation.

Administration, Oral↗
PubMed1997

Agmatine activation of nitric oxide synthase in endothelial cells.

Agmatine is a product of arginine decarboxylation. Systemic infusion of agmatine into rats causes hypotension. This effect could be due either to a central action of agmatine (a clonidine displacing substance), or to a direct effect of agmatine on cells of blood vessel walls, which induces them to cause vasodilatation, or both. In this study, we examined the effects of agmatine on endothelial cell function by using cultured bovine pulmonary artery endothelial cells. Agmatine stimulated nitrite production three-fold above basal nitrite formation by endothelial cells. The increased nitrite production by agmatine was inhibited by idazoxan but not by yohimbine. Agmatine displaced [3H]-idazoxan from endothelial cell membranes and was found to induce transients in the cytosolic calcium of endothelial cells. The transients could be downregulated by repeated exposure to agmatine but were not affected by pretreatment with norepinephrine. These results suggest that agmatine can bind to a cell surface imidazoline receptor on endothelial cells and can stimulate nitric oxide production by increasing cytosolic calcium. Therefore, agmatine appears to act directly on endothelial cells to increase the synthesis of nitric oxide, a vasodilatory substance.

Agmatine↗
PubMed1997

Prevention of progression of nephropathy.

Several factors have been implicated in progressive nephropathy. In a recent clinical trial, the Modification of Diet in Renal Disease (MDRD) study, six factors out of 41 examined were found to be predictors of progression of renal disease: proteinuria, mean arterial pressure, black race, diagnosis of polycystic kidney disease, serum transferin levels, and serum high density lipoprotein (HDL) cholesterol. Hypertension as a factor in progressive renal disease has been documented in both animal and human studies. Patients in the MDRD study were randomly assigned to two levels of blood pressure control: usual (mean arterial pressure of 107 mmHg) or low (mean arterial pressure of 92 mmHg). Patients with proteinuria > 1 g/day assigned to the low blood pressure goal had a slower mean decline in GFR as compared to patients assigned to the usual blood pressure goal. Recommendations derived from the results of the MDRD study specify that in patients with proteinuria > 1 g/day, a mean arterial pressure goal of 92 mmHg or less (equivalent to a blood pressure of 125/75 mmHg) should be the target. Several studies have suggested that dietary protein restriction benefits patients with chronic renal disease. The MDRD study found that dietary protein restriction slowed disease progression in patients with more advanced renal disease (GFR 13-24 ml/min) at the onset of the trial. In summary, current evidence indicates that a decrease in proteinuria, lowering of systemic blood pressure, and a decreased intake of protein ameliorate the rate of progression (loss of GFR) in patients with chronic renal disease.

Dietary Proteins↗
PubMed1997

Oxygen radicals and renal diseases.

Reactive oxygen metabolites (superoxide, hydrogen peroxide, hydroxyl radical, and hypochlorous acid) are important mediators of renal damage in acute renal failure and glomerular and tubulointerstitial diseases. The role of these oxygen metabolites in the above entities is discussed, and the effects of antioxidants and scavengers of O2 radicals are considered. The role of oxygen radicals in the regulation of gene transcription is also considered.

Animals↗
PubMed1997

Comparative study of ACE inhibitors and angiotensin II receptor antagonists in interstitial scarring.

Many of the pathophysiologic events associated with kidney disease are driven by angiotensin II. Irrespective of the etiology, many kidney diseases lead to tubulointerstitial inflammation, fibrosis and loss of renal function. Contributors to the process of tubulointerstitial fibrosis include monocyte/macrophage infiltration, the synthesis of profibrotic cytokines such as transforming growth factor beta 1 (TGF-beta 1), interstitial myofibroblast proliferation, and clusterin expression. These processes are ameliorated by angiotensin converting enzyme (ACE) inhibition. Blockade of the angiotensin II receptor (AT-1) impaired fibroblast proliferation, consequent differentiation into myofibroblasts, and the synthesis of TGF-beta 1, but did not prevent monocyte infiltration. TGF-beta 1 synthesis or fibroblast proliferation but prevented the differentiation of fibroblasts into myofibroblasts and blocked clusterin expression. The nuclear factor-kappa B (NF-kappa B) family of transcription factors regulates genes involved in inflammation, proliferation and differentiation. ACE inhibition, AT-1 and AT-2 receptor blockade each differentially attenuated NF-kappa B isotype activation. The changes in NF-kappa B isotype may account for the variation seen in the pharmacologic effect of angiotensin II formation or action on the fibrotic process. When considering therapeutic options to prevent renal disease progression, one must be aware of the impact of transcription factors on the injured kidney and the consequent changes in cell infiltration, proliferation and differentiation.

Angiotensin II↗
PubMed1996

Quantitation of the putative neurotransmitter agmatine as the hexafluoroacetylacetonate derivative by stable isotope dilution gas chromatography and negative-ion chemical ionization mass spectrometry.

A method is described for detection and quantitation of agmatine [4-(aminobutyl)guanidine] by gas chromatography/negative-ion chemical ionization/mass spectrometry after derivatization with hexafluoroacetylacetone. The lower limit of detection of the derivative was about 25 fmol on-column. For quantitative studies of agmatine content in biological samples, a procedure utilizing an internal standard ([15N4]agmatine prepared from [15N4]arginine) and an extraction step had a lower limit of detection of about 15 pmol for total sample content. Agmatine content was measured in rat tissue samples and normalized to protein content. Kidney and spleen samples exhibited the greatest content of agmatine per unit protein mass but agmatine was also detected in pancreatic islets and brain regions (cerebellum and cerebral cortex). On the basis of these measurements, it is estimated that the pancreatic islet intracellular agmatine concentration may exceed 1 microM. The sensitive and highly specific means of detection and quantitation provided by mass spectrometry may be useful in investigating the physiological role of agmatine in mammalian systems.

Agmatine↗
PubMed1996

Bone disease in long-term dialysis.

We reviewed the clinical features, laboratory findings, and skeletal abnormalities of six patients who have been on dialysis therapy for 12 to 20 years (average, 16.7 years). Hemodialysis has been the major therapeutic modality in five of the six individuals. Ages of the patients ranged from 28 to 67 years (mean, 44.5). Bone biopsy specimens were available for five of the patients. In three of these, the predominant changes in bone were those of osteitis fibrosa. In two patients with severe osteitis fibrosa, there was a decrease in height. Two patients had predominantly osteomalacia, but in one of these, the condition was noted before the initiation of 13 years of chronic ambulatory peritoneal dialysis, supplanted 2 years ago by hemodialysis. Total parathyroidectomies with implants of parathyroid tissue in the forearm were performed in four of the six patients. All four had, and continue to have, markedly elevated levels of parathyroid hormone (PTH). Symptoms and signs of amyloidosis of bone have occurred in all six patients, including carpal tunnel syndrome in two, bone cysts in three, and presumptive tendon involvement of the shoulder in one patient. The pathogenesis of hyperparathyroidism is described briefly, and appropriate treatment is summarized.

Adult↗