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Biomedical subjects

A Fogo

Publications and source records attributed to A Fogo.

At least 91 records · Page 5Linked to original sources
PubMed1991

Evidence for a pathogenic linkage between glomerular hypertrophy and sclerosis.

Primary renal disease of immunologic or nonimmunologic mechanisms induces loss of substantial nephron population. It is presumed that the initial loss of functioning nephrons causes alterations of function and metabolism in remnant nephrons, which per se are self-inflictive, leading to further loss of nephrons. The ultimate outcome of this vicious cycle is the end-stage kidney. The potential role of various pathophysiologic mechanisms has been explored. These studies have shown a tight link between glomerular hypertrophy and sclerosis. Analysis of individual glomeruli show a biphasic pattern of these two parameters. Early development of glomerular sclerosis takes place along with the hypertrophy of the glomerulus, and further advancement of sclerosis occurs with shrinkage in glomerular size. Thus, we propose that, after initial nephron loss, the remnant glomeruli are exposed to increased growth-promoting factors, which are self-inflictive in nature due to their capacity to produce excessive amounts of extracellular matrix in the mesangial area. When the excessive matrix obliterates the glomerular capillary lumen, a typical sclerotic lesion appears. This is a vicious and accelerating process, since sclerosis induces further reduction in the nephron population, thereby imposing greater influence of growth-promoting factors even on glomeruli that are initially resistant.

Aging↗
PubMed1991

Cause of variable therapeutic efficiency of angiotensin converting enzyme inhibitor on glomerular lesions.

We tested the effect of angiotensin I converting enzyme inhibitor (ACEI) on established glomerular sclerosis. Starting eight weeks after subtotal nephrectomy (sNPX), rats were given enalapril for four weeks in a dose of 50 (Group II, N = 5) or 200 mg/liter drinking water (Group III, N = 5). A third group of sNPX rats not given ACEI served as control (Group I, N = 10). Glomerular sclerosis index (S1, 0 to 4 scale) was assessed three-dimensionally on serial thin sections for individual glomeruli at biopsy (Bx, 8 weeks), and divided into four different ranks of severity and compared to autopsy (Ax, 12 weeks). In Group I control rats, 48% of the glomeruli at Bx had SI between 0 and 1 (rank 1, average: 0.49 +/- 0.06), 36% between 1 and 2 (rank 2, average: 1.53 +/- 0.06), 9% between 2 and 3 (rank 3, average: 2.45 +/- 0.12) and 7% between 3 and 4 (rank 4, average: 3.54 +/- 0.10). Glomeruli of the same rats at Ax were ranked according to severity of sclerosis, and then divided into percentile groups, corresponding to the percent of distribution at Bx. The 48% least sclerotic glomeruli at Ax had average SI of 0.69 +/- 0.08, the next 36% 2.58 +/- 0.11, and next 9% 3.97 +/- 0.02 and the most sclerotic 7% 4.00 +/- 0.00. Thus, sclerosis advanced during the last four weeks after biopsy in all glomeruli, with more accelerated progression occurring toward later stages of sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Glucocorticoid activates glomerular antioxidant enzymes and protects glomeruli from oxidant injuries.

We examined the effect of glucocorticoid on intrinsic glomerular antioxidant enzyme (AOE) activities. Munich-Wistar rats were treated with daily i.p. injection of vehicle or methylprednisolone [MP, 15 mg/kg body wt, (MP15)] either for three days or nine days. Glomeruli isolated from rats given MP15 had significantly higher activities of total (T-) and manganese (Mn-) superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase than vehicle-treated rats (P less than 0.05). MP15-treated rats were subjected to intrarenal arterial infusion of hydrogen peroxide (35 mumol over 1 hr). Values for urinary protein excretion rate (UprV) after hydrogen peroxide infusion were markedly lower in rats pretreated with MP15 for both three days and nine days than in untreated rats (109 +/- 18 and 55 +/- 24 vs. 416 +/- 73 micrograms/min, respectively, both P less than 0.005). To test whether the same therapeutic intervention attenuates reactive oxygen species (ROS)-mediated glomerular injury in another model, rats given a single i.v. dose of puromycin aminonucleoside (PAN) (50 mg/kg body wt) were treated with daily i.p. injection of vehicle or MP15. Two days after PAN administration, when compared to vehicle-treated controls, PAN rats given MP15 had significantly higher activities of Mn-SOD, GSH-Px and catalase. After eight days of PAN injection, T- and Mn-SOD activities were, likewise, significantly higher in MP15- than vehicle-treated PAN rats. PAN rats given MP15 also had substantially less proteinuria, compared to PAN rats given vehicle alone, UprV averaging 32.3 +/- 9.4 versus 159.0 +/- 13.8 mg/24 hr (P less than 0.05). Elevated glomerular malondialdehyde (MDA) level characteristic of PAN rats was absent in rats treated with MP15. Moreover, epithelial foot process fusion and cell vacuolization seen in vehicle-treated PAN rats were markedly attenuated in MP15-treated PAN rats. These data indicate that the mechanism for therapeutic effect of glucocorticoids on ROS-mediated renal injuries includes an enhancement of endogenous glomerular AOE activities, which attenuates lipid peroxidation of glomerular tissue.

Animals↗
PubMed1991

Complement activation retards resolution of acute ischemic renal failure in the rat.

We investigated the role of complement activation on the resolution of acute ischemic renal failure in the rat. Acute renal failure was induced by clamping of the renal arteries of Sprague-Dawley rats for 45 minutes (Day 0). On subsequent days, groups of rats with acute renal failure were exposed to daily zymosan infusion (an activator of the complement system), or to blood incubated with cuprophane (CUP) or polyacrylonitrile (PAN) dialysis membranes. We serially measured the change in BUN daily, glomerular filtration rate and 24-hour proteinuria on Day 3 and Day 5 following ischemia. On Day 6, the animals were sacrificed and their kidneys examined histologically. Zymosan and cuprophane exposed rats had a significant delay in the recovery of renal failure, reduced glomerular filtration rate, and histologically had more neutrophil infiltration than control or PAN exposed animals. To investigate the potential pathophysiology of these observations, we assessed the response of zymosan-exposed rats to infusion of deferoxamine (DFO), a potent inhibitor of hydroxyl radical formation (OH.). Infusion of DFO prior to zymosan significantly improved recovery of renal function. We also measured urinary thromboxane B2 levels in these groups of rats. While the groups of rats exposed to zymosan had the highest levels of thromboxane B2, these levels were not different between the groups exposed to zymosan alone, or to zymosan and DFO. These observations suggest a role for hydroxyl radicals in the prolongation of renal failure in this model. Taken together, these findings may have implications for the dialytic intervention in patients with acute renal failure.

Acute Kidney Injury↗
PubMed1991

Functional significance of leukotriene B4 in normal and glomerulonephritic kidneys.

Leukotriene B4 (LTB4) is the major 5-lipoxgenase product released during early experimental glomerulonephritis. To test its functional relevance, its actions in the normal rat kidney and its influence on renal function in the heterologous phase of mild nephrotoxic serum-induced glomerular injury were examined. Intrarenal administration of leukotriene B4 resulted in mild vasorelaxant and natriuretic responses which were shared by 12(R)-hydroxyeicosatetraenoic acid but not 12(S)-leukotriene B4 or 12(S)-hydroxyeicosatetraenoic acid, suggesting activation of a common recognition site with a requirement for 12(R) stereochemistry. The polymorphonuclear cell-specific activator, N-formyl-Met-Leu-Phe, stimulated leukotriene B4 production from isolated perfused kidneys harvested from nephrotoxic serum-treated rats to a significantly greater degree than from control animals treated with nonimmune rabbit serum. The renal production of leukotriene B4 correlated directly and strongly (r = 0.79, P less than 0.01) with renal myeloperoxidase activity, suggesting interdependence of leukotriene B4 generation and polymorphonuclear cell infiltration. In vivo, intrarenal administration of leukotriene B4 to rats with mild nephrotoxic serum-induced injury was associated with an increase in polymorphonuclear cell infiltration, reduction in renal plasma flow rate, and marked exacerbation of the fall in glomerular filtration rate, the latter correlating strongly with the number of infiltrating polymorphonuclear cells/glomerulus, whereas inhibition of 5-lipoxygenase led to preservation of glomerular filtration rate and abrogation of proteinuria. Thus, although devoid of vasoconstrictor actions in the normal kidney, increased intrarenal generation of leukotriene B4 during early nephrotoxic serum-induced glomerular injury amplifies leukocyte-dependent reductions in glomerular perfusion and filtration rates, likely due to enhancement of polymorphonuclear cell recruitment/activation.

Animals↗
PubMed1991

Reactive oxygen metabolites cause massive, reversible proteinuria and glomerular sieving defect without apparent ultrastructural abnormality.

To identify the specific in vivo renal effect of reactive oxygen species (ROS), hydrogen peroxide (H2O2) was infused directly into the left renal artery in Munich-Wistar rats. H2O2 (5 to 50 mumol over 1 h) induced a dose-dependent increase in urine protein excretion rate in infused kidneys, reaching a maximum at the dose of 35 mumol (on average, a 60-fold increase from baseline). The H2O2 (35 mumol)-induced proteinuria peaked over 1 h and completely normalized by 24 h after the infusion. Electrophoresis revealed that the urine protein is primarily of glomerular origin. Fractional clearances of graded-size neutral dextran of larger molecular radii, an index of glomerular size selectivity, were significantly and substantially elevated immediately but normalized by 24 h after the infusion. GFR and RPF rate remained unchanged throughout the entire time course examined. The H2O2-induced proteinuria was largely prevented by pretreatment with catalase (20 mg, iv) or deferoxamine (30 mg/100 g body wt, iv). Thus, iron-dependent metabolites of hydrogen peroxide appear to be involved in this proteinuria and glomerular size-selective defect. Light and electron microscopy, including determination of anionic site density at lamina rara externa of glomerular capillary wall by polyethyleneimine staining, did not reveal any appreciable abnormality throughout the study period, including at the peak of proteinuria. Thus, ROS can cause massive, reversible proteinuria by inducing a molecular size-selectivity defect of the glomerular capillary wall without apparent ultrastructural abnormalities. The results raise the possibilities: (1) that persistent proteinuria of a variety of renal diseases may reflect persistence of pathogenic ROS acting on glomeruli because the potent proteinuric effect of ROS can be transient (2) that the light and electron microscopy abnormalities in glomeruli of ROS-induced renal injuries reported thus far may have no direct causal linkage to proteinuria; and, finally, (3) ROS-induced reversible proteinuria may relate to the mechanism of clinical functional proteinuria, which involves increased oxygen and ROS metabolism, e.g., exercise-induced proteinuria.

Animals↗
PubMed1990

Physiologic and pathologic alterations associated with ultrasonically generated shock waves.

Kidneys of 25 dogs were treated with ultrasonic shock waves and examined for both physiologic and pathologic changes. The number of pulses ranged from 2,000 to 8,000. The rate of the shock waves varied from one to 20 pulses per second. The difference in pulse rate did not affect the changes seen either acutely or in the delayed examination of the kidneys during the repair process. The physiologic and pathologic changes which occurred involved the renal tubule to a greater degree than the glomerulus. These alterations were resolving by one week following exposure to the shock waves.

Animals↗
PubMed1990

Glomerular hypertrophy in minimal change disease predicts subsequent progression to focal glomerular sclerosis.

The study sought a diagnostic clue to identify the group of pediatric patients with apparent minimal change disease who subsequently develop focal glomerular sclerosis (FGS). Review of all renal biopsy material at our institutions identified 42 pediatric patients who met the standard criteria for minimal change disease (MCD) on initial biopsies. Of those, 10 deteriorated clinically and on rebiopsy showed focal glomerular sclerosis (FGS). The initial renal biopsies of these 10 patients were analyzed morphometrically to determine the mean glomerular tuft area (GA). The results were compared to those of the remaining 32 patients whose subsequent benign clinical course was consistent with MCD, and to randomly selected, age-matched autopsy controls without renal disease (CONT, N = 10). The mean age was comparable among the three groups studied. Separate groups of adult (N = 12) and pediatric (N = 18) patients with initial biopsies with FGS were also studied. The initial biopsy of pediatric patients who subsequently showed FGS (rebiopsy performed on average 3.3 years later) had an average GA of 13.5 x 10(-3) mm2, 76% larger than glomeruli from children with MCD (7.7 x 10(-3) mm2, P less than 0.0005) and 62% larger than CONT (8.4 x 10(-3) mm2, P less than 0.005). Patients with FGS on initial biopsy, whether adult or pediatric, also had significantly larger GA than the age-matched MCD or CONT groups. Evaluation of GA in all the 42 pediatric biopsies with initial MCD further showed that in 23 patients GA was equal to or smaller than the CONT average.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Importance of angiogenic action of angiotensin II in the glomerular growth of maturing kidneys.

We studied the effect of three antihypertensive drugs on the growth of glomeruli in four- to five-week-old Munich-Wistar rats (N = 24), which were undergoing rapid maturation processes. Young rats were given an angiotensin converting enzyme inhibitor (ACEI, enalapril, 50 mg/liter drinking water), verapamil (50 mg/liter) or hydralazine (80 mg/liter) or no treatment for six weeks. Body weight increased comparably in the treatment groups and age-matched controls, reaching on average 197 +/- 11, 214 +/- 12 and 198 +/- 3 g in ACEI-, verapamil- and hydralazine-treated rats, respectively, versus 218 +/- 6 g in control rats. Glomerular hemodynamic patterns, including glomerular capillary pressure, measured in maturing rats after one and six weeks of ACEI treatment were unaffected by ACEI. Mean planar area of glomeruli (PAmean) achieved was smaller than control in ACEI rats (6.60 +/- 0.20 x 10(-3) mm2 vs. 5.37 +/- 0.22, respectively, P less than 0.005), but not in rats treated with other antihypertensive drugs. Furthermore, the maturational PAmean increase in rats given ACEI for six weeks was, on average, only half of that achieved by age-matched controls not given ACEI, in contrast to normal maturational growth with hydralazine or verapamil (29% increase in PAmean from normal baseline in ACEI vs. 52%, 53% and 59% increases in verapamil, hydralazine and control, respectively). In contrast, comparable PAmean values were found in adults with (7.08 +/- 0.22 x 10(-3)mm2, N = 6) and without (6.98 +/- 0.33 x 10(-3)mm2, N = 6) ACEI treatment given for six weeks. Therefore, ACEI, but not verapamil and hydralazine, causes growth retardation in maturing glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1990

Mechanism of the unique susceptibility of deep cortical glomeruli of maturing kidneys to severe focal glomerular sclerosis.

The alterations in single glomerular hemodynamics, glomerular size, and development of glomerular sclerosis after subtotal nephrectomy were assessed in approximately 32-d-old young and greater than 3-mo-old adult Munich-Wistar rats. In 6 wk, young rats developed more pronounced glomerular sclerosis and more marked elevation in blood urea nitrogen. The deep (versus superficial) cortical region of young rats was characterized by having a greater number of glomeruli with advanced sclerosis. Single nephron glomerular filtration rate of superficial glomeruli of the young increased to a much greater extent than whole kidney glomerular filtration rate, whereas there were comparable post-subtotal nephrectomy increases in whole kidney glomerular filtration rate in these two age groups, indicating that the deep glomeruli were exposed to a lesser hemodynamic load than were the superficial. Since the remnant nephrons of young and adult rats achieved equally high glomerular pressures and comparably large glomerular size shortly after subtotal nephrectomy, the unique susceptibility of young glomeruli to sclerosis is attributed to the intrinsic property of these glomeruli, rather than the abnormal hemodynamics or stimuli promoting hypertrophy and mesangial matrix accumulation imposed upon the glomeruli.

Age Factors↗
PubMed1989

Effects of antihypertensive drugs on glomerular morphology.

We quantitated the glomerular size and the degree of sclerosis simultaneously in individual glomeruli with the use of three-dimensional histological analysis on serial sections obtained from remnant kidneys with highly heterogeneous glomerular lesions after subtotal nephrectomy (sNPX). Four to six weeks after sNPX (Group I, N = 7), 90% of glomeruli had mild sclerosis (sclerosis index, SI; less than 1.5 on a 0 to 4 scale) with a strong positive correlation between the maximum planar area of glomerulus (PAmax) versus SI. Twelve weeks after sNPX (Group II, N = 6) more than 50% of glomeruli had advanced sclerosis (average SI:1.88), and a significant positive correlation was again found between PAmax and SI in glomeruli with mild to modest sclerosis (SI less than 1.5), whereas these two variables were correlated inversely in glomeruli with advanced sclerosis. Administration of enalapril (50 mg/liter drinking water) or hydralazine (200 mg/liter) + hydrochlorothiazide (50 mg/liter) for 12 weeks (Group III, N = 12) markedly attenuated the sclerosis to comparable degrees (average SI: 0.15 vs. 0.22). The former antihypertensive therapy decreased glomerular capillary hydraulic pressure (PGC) to normal range, whereas the latter triple drug therapy was largely without effect on PGC. Of note, the positive correlation between SI and PAmax remained unaffected by these anti-hypertensive drugs. SI of the glomeruli from both treated groups was expressed as a first-order function of PAmax. The correlation coefficient is identical to that found in non-treated Group II remnant glomeruli, so that the degree of sclerosis is mathematically uniquely correlated with the glomerular size, regardless of drug treatment. Thus, within a given remnant kidney, the magnitude of glomerular hypertrophy has a direct correlation with the degree of sclerosis, while the altered glomerular hemodynamic pattern has little modulatory role in determining the magnitude of this hypertrophy. Enalapril and triple drug therapy, at equi-depressor doses in regard to systemic blood pressure, had identical potency in sparing glomerular structure. The primary determinant for this antisclerotic potency appears to be related to the drugs' potency to inhibit glomerular growth rather than an effect on the abnormal hemodynamics which develop in the glomerulus.

Animals↗
PubMed1989

Glomerular hemodynamic changes vs. hypertrophy in experimental glomerular sclerosis.

In a variety of recent studies in animals with chronic renal diseases, investigators have found a tight correlation between the elevation in glomerular pressures and flows versus glomerular hypertrophy. To investigate a possible causal link between the glomerular hyperfunction and hypertrophy, we studied the functional and morphological sequelae of nephrectomy and those of unilateral ureteral diversion (UD) into the peritoneal cavity (that is, removal of renal clearance function while keeping the kidney tissue in situ). In all nine experimental groups of 54 Munich-Wistar rats, 2/3 of the renal mass was removed from the left kidney by ligation of two or three branches of the left renal artery. In addition, right nephrectomy (NPX) was performed in Groups 1B, 2B and 3B or UD in Groups 1C, 2C and 3C. The right kidney was left untouched in control groups, Groups 1A, 2A and 3A. Micropuncture measurements and histological studies were performed at four days (Groups 1A, 1B and 1C), two weeks (Groups 2A, 2B and 2C) or four weeks (Groups 3A, 3B and 3C). At both four days and two weeks, NPX and UD groups had marked and comparable degrees of glomerular hypertension, hyperperfusion and hyperfiltration compared to the control group in the left kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗