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Biomedical subjects

B M Brenner

Publications and source records attributed to B M Brenner.

At least 217 records · Page 12Linked to original sources
PubMed1985

Converting enzyme inhibitor therapy limits progressive glomerular injury in rats with renal insufficiency.

Sustained increases in glomerular capillary pressure and flow accompany systemic hypertension in rats that have undergone extensive ablation of the renal mass. These intrarenal hemodynamic changes are, in turn, associated with the progressive development of proteinuria and glomerular sclerosis, leading ultimately to failure of remnant nephron units. The efficacy of antihypertensive therapy with enalapril was evaluated in this animal model of chronic renal insufficiency. A dose of enalapril sufficient to prevent systemic hypertension normalized the glomerular capillary pressure without reducing the glomerular filtration rate in the remnant kidney. Maintenance of normal capillary pressure markedly reduced the development of proteinuria and sclerotic lesions in remnant glomeruli. These results suggest that antihypertensive therapy directed at reducing the glomerular capillary pressure could retard the progressive loss of renal function in patients whose functional renal mass has been reduced by disease.

Animals↗
PubMed1985

Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy.

Six groups of Munich-Wistar rats underwent micropuncture study 2-10 weeks and morphologic studies 11-13 months after induction of streptozotocin diabetes or after sham treatment. Diabetic rats received diets containing 6% (group D6), 12% (D12), or 50% protein (D50) and were maintained under similar conditions of moderate hyperglycemia by daily injections of ultralente insulin. Age- and weight-matched normal control rats were also given 6% (Group N6), 12% (N12), or 50% protein (N50). Kidney weight, whole-kidney and single-nephron glomerular filtration rate, glomerular plasma flow, and mean glomerular transcapillary hydraulic pressure difference were higher in D50 rats than in all other groups and predisposed this group to marked and progressive albuminuria. Likewise, histological examination of the kidneys disclosed areas of sclerosis in 19.6% of glomeruli in D50 rats; the frequency of such lesions was less than 2.5% in all other groups. These findings indicate that the metabolic disorder seen in stable, moderately hyperglycemic diabetic rats does not lead to glomerulopathy as long as elevations in glomerular pressures and flows are prevented.

Animals↗
PubMed1985

Nephron adaptation to renal injury or ablation.

In early stages of permanent renal injury or extensive ablation, structural and functional adaptations associated with hypertrophy partially compensate for nephron losses. Glomerulotubular balance is maintained in these conditioned nephrons by intrinsic tubule and peritubular capillary adaptations that parallel single nephron glomerular filtration rate (SNGFR). Studies of Na+-H+ exchange in renal cortical brush border membrane vesicles indicate that tubule functional adaptation is not tied to loss of renal mass per se but rather to factors such as dietary protein content that set the level of SNGFR. Likewise, the structural heterogeneity that follows chronic renal injury or extreme ablation of renal mass is less a consequence of nephron injury than of adaptation linked to dietary protein intake. Indeed, since dietary protein restriction blunts the need for compensatory glomerular hyperfiltration, there is neither a stimulus for nephron hypertrophy nor for enhanced tubule ion and fluid transport. In rats with remnant kidneys, experimentally induced diabetes mellitus, or severe hypertension, increases in glomerular pressures and flows precede proteinuria, glomerular sclerosis, and azotemia. Protein restriction prevents these hemodynamic adaptations as well as the late complications. Similar conclusions appear to be applicable to a wide spectrum of clinical circumstances characterized by reduced nephron number.

Animals↗
PubMed1985

Heteroporous model of glomerular size selectivity: application to normal and nephrotic humans.

A heteroporous model of the glomerular filtration barrier was developed and used to interpret dextransieving data in healthy volunteers (normal controls), in patients with nephrotic range proteinuria (grouped as grades I-III, according to severity), and in a group of previously nephrotic patients whose proteinuria was in remission ("resolved controls"). Several hypothetical pore-size distributions were compared in terms of their ability to describe the selective increases in the fractional clearance of large dextrans observed with increasing severity of proteinuria. The most successful model examined was based on the assumption that the major portion of the capillary wall functions as an isoporous membrane, but that a small fraction of the filtrate passes through pores that are unable to discriminate among dextrans of different sizes. The value of the membrane parameter that reflects the relative importance of the nonselective pores was found to increase in parallel with the fractional clearance of immunoglobulin G; it increased progressively in going from normal controls to resolved controls to grades I-III nephrotics. The observed patterns of protein excretion could not, however, be explained entirely by a loss of glomerular size selectivity. Variations in membrane selectivity on the basis of molecular charge and/or molecular configuration are also likely to have been important.

Glomerular Filtration Rate↗
PubMed1985

Identification and characterization of leukotriene C4 receptors in isolated rat renal glomeruli.

The immediate reduction of renal blood flow and glomerular filtration rate in response to intravenous infusion of leukotriene C4 in the rat prompted an analysis of isolated rat renal glomeruli for the presence of specific receptors for leukotriene C4. Specific binding of [3H]leukotriene C4 to glomeruli increased in a time-dependent manner, reached equilibrium after 60 minutes of incubation at 4 degrees C, and was 80% reversible upon addition of excess unlabeled leukotriene C4 at equilibrium. Specific binding of [3H]leukotriene C4 to glomeruli increased in a dose-dependent manner, approaching saturation at concentrations of 40-60 nM. Inhibition of binding of [3H]leukotriene C4 with increasing concentrations of unlabeled leukotriene C4 was dose dependent. The equilibrium dissociation constant for [3H]leukotriene C4 binding to glomeruli, calculated from saturation and competitive binding-inhibition studies, was 25 +/- 7 nM and 35 +/- 16 nM (mean +/- SEM), respectively, and glomerular leukotriene C4 receptor density was 8.5 +/- 1.5 and 9.0 +/- 3.0 pmol/mg protein, respectively. The other natural vasoactive sulfidopeptide leukotrienes, leukotriene D4 and leukotriene E4, the chemotactic agent, leukotriene B4, and the sulfidopeptide leukotriene antagonist, FPL 55712, competed for the receptor at concentrations 2-3 orders of magnitude higher than the homoligand, leukotriene C4. The binding and specificity characteristics of the glomerular leukotriene C4 receptor are similar to those previously reported for the DDT1 nonvascular smooth muscle cell line derived from hamster vas deferens, for guinea pig ileum smooth muscle, and for a subcellular fraction of rat lung homogenate, and represent the first characterization of such a receptor in a vascular tissue.

Animals↗
PubMed1985

Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass.

Micropuncture and morphologic studies were performed in four groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 3 received no specific therapy. Groups 2 and 4 were treated with the angiotensin I converting enzyme inhibitor, enalapril, 50 mg/liter of which was put in their drinking water. All rats were fed standard chow. Groups 1 and 2 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure difference and glomerular plasma flow rate. In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained the mean glomerular transcapillary hydraulic pressure gradient at near-normal levels without significantly compromising SNGFR and the glomerular capillary plasma flow rate, as compared with untreated group 1 rats. Groups 3 and 4 were studied 8 wk after renal ablation. Untreated group 3 rats demonstrated persistent systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and segmental sclerosis. In group 4 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 8-wk period and significantly limited the development of proteinuria and glomerular lesions. These studies suggest that control of glomerular hypertension effectively limits glomerular injury in rats with renal ablation, and further support the view that glomerular hemodynamic changes mediate progressive renal injury when nephron number is reduced.

Animals↗
PubMed1985

Physiologic regulation of atrial natriuretic peptide receptors in rat renal glomeruli.

Isolated rat renal glomeruli and cultured glomerular mesangial and epithelial cells were examined for atrial natriuretic peptide (ANP) receptors, and for ANP-stimulated cyclic guanosine monophosphate (cGMP) generation. In glomeruli from normal rats, human (1-28) 125I-ANP bound to a single population of high affinity receptors with a mean equilibrium dissociation constant of 0.46 nM. Human (1-28) ANP markedly stimulated cGMP generation, but not cAMP generation in normal rat glomeruli. Analogues of ANP that bound to the glomerular ANP receptor with high affinity stimulated cGMP accumulation, whereas the (13-28) ANP fragment, which failed to bind to the receptor, was devoid of functional activity. Cell surface receptors for ANP were expressed on cultured glomerular mesangial but not epithelial cells, and appreciable ANP-stimulated cGMP accumulation was elicited only in mesangial cells. Approximately 12,000 ANP receptor sites were present per mesangial cell, with an average value for the equilibrium dissociation constant of 0.22 nM. Feeding of a low-salt diet to rats for 2 wk resulted in marked up regulation of the glomerular ANP receptor density to a mean of 426 fmol/mg protein, compared with 116 fmol/mg in rats given a high-salt diet. A modest reduction in the affinity of glomerular ANP receptors was also observed in rats fed the low-salt diet. ANP-stimulated cGMP generation in glomeruli did not change with alterations in salt intake. We conclude that high salt feeding in the rat results in reduced glomerular ANP receptor density relative to values in salt restricted rats. Furthermore, the mesangial cell is a principal target for ANP binding in the glomerulus.

Amino Acid Sequence↗
PubMed1984

Glomerular actions of angiotensin II.

An abundance of evidence suggests that glomerular ultrafiltration is significantly influenced by alterations in circulating or local concentrations of a variety of vasoactive substances. Angiotensin II regulates whole kidney glomerular filtration rate by influencing one or more of the determinants of single nephron glomerular filtration rate, particularly the ultrafiltration coefficient and glomerular plasma flow rate. The glomerular mesangial cell may be an important target for angiotensin II by virtue of its ability to contract and thereby reduce glomerular capillary surface area and ultrafiltration coefficient. These control mechanisms are not only important under physiologic conditions but they may also be activated by a variety of insults and thereby contribute to the decrease in glomerular filtration rate observed in a broad spectrum of renal disease.

Angiotensin II↗
PubMed1984

Comparative effects of propranolol and nadolol on renal blood flow in normal rats and rats with congestive heart failure.

Mean arterial blood pressure (MAP), heart rate (HR), renal blood flow (RBF), and renal vascular resistance (RVR) were determined before and during an infusion of propranolol (18 mg/kg/hr) or nadolol (30 mg/kg/hr) in anesthetized Munich-Wistar rats with normal cardiac function. Eight rats treated with propranolol had significant reductions in MAP (110 to 98 mm Hg; p less than 0.05) and HR (316 to 242 bpm; p less than 0.01), accompanied by a 24% decrease in RBF (5.9 to 4.5 ml/min; p less than 0.05) and a 22% increase in RVR (19.4 to 23.7 mm Hg/ml/min; p less than 0.05). Although nadolol also reduced MAP (104 to 93 mm Hg; p less than 0.01) and HR (315 to 268 bpm; p less than 0.05) in eight other rats, RBF and RVR remained unchanged from baseline levels. Thus, despite similar decrements in MAP and HR, propranolol decreased renal perfusion, whereas nadolol maintained it in animals with noninfarcted myocardium. These parameters were also evaluated in rats with congestive heart failure induced by myocardial infarction at least 3 weeks prior to their receiving either propranolol (18 mg/kg/hr; n = 6) or nadolol (30 mg/kg/hr; n = 6). In the basal state, rats with congestive heart failure had significantly (p less than 0.05) lower MAP, HR, and RBF and higher (p less than 0.01) RVR compared with control rats. Propranolol and nadolol induced comparable falls (p less than 0.05) in MAP and HR. Whereas RBF tended to fall with propranolol (3.3 to 2.4 ml/min), renal perfusion was well maintained with nadolol (3.4 to 3.8 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1984

Hypertension and proteinuria: long-term sequelae of uninephrectomy in humans.

Renal function and blood pressure were assessed in 52 renal allograft donors 10 years or more following uninephrectomy, and their current function compared to their pre-uninephrectomy function as well as to age- and sex-matched control subjects consisting of inpatient potential renal donors and a normal "outpatient" population. The results show no significant deterioration in renal function as determined by serum creatinine or creatinine clearance, as a function of years post-uninephrectomy or age at the time of donation. A higher incidence of proteinuria and hypertension was found in male donors as compared to their pre-uninephrectomy values and to age- and sex-matched, inpatient and outpatient control subjects. Female donors had increased proteinuria when compared to pre-uninephrectomy and to age-matched, inpatient potential donors. However, the extent of proteinuria and hypertension was not significantly different from outpatient age-matched females with two kidneys. In our population, uninephrectomy is associated with mild proteinuria and hypertension.

Adult↗
PubMed1984

Reduced glomerular angiotensin II receptor density in early untreated diabetes mellitus in the rat.

Density and affinity of glomerular angiotensin II (ANG II) receptors were determined in normal, untreated, and insulin-treated streptozotocin-diabetic rats 3-4 wk after the onset of diabetes mellitus. With low, intermediate, and high salt intake, angiotensin II receptor density varied inversely with the plasma renin concentration (PRC) in normal, insulin-treated, and untreated diabetic rats. PRC values with all three dietary regimens were lower in the untreated diabetic rats when compared with the other groups. Despite lower plasma renin concentration, however, untreated diabetic rats were also found to have significantly lower glomerular ANG II receptor concentrations at all levels of salt intake. On a normal salt intake, glomerular ANG II receptor density was reduced significantly in untreated diabetic rats (853 +/- 74 (SE) fmol/mg protein), compared with insulin-treated diabetic rats (1,185 +/- 118 fmol/mg) and normal controls (1,058 +/- 83 fmol/mg). ANG II receptor affinity did not change with alternations in salt intake or degree of diabetic control. Reduced glomerular ANG II receptor density in the presence of a suppressed renin-ANG II axis may underlie the altered renal vascular responsiveness to ANG II known to occur in diabetes mellitus.

Angiotensin II↗
PubMed1984

Renal and systemic hemodynamic responses to intravenous infusion of leukotriene C4 in the rat.

We studied the systemic and renal hemodynamic effects of leukotriene C4 (2 micrograms/kg per min for 5 minutes, iv) in the rat. During the period of its infusion, leukotriene C4 produced a significant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, as measured by electromagnetic flow probes. These effects were abolished by FPL55712 , a putative antagonist of sulfidopeptide leukotrienes, but not by saralasin or indomethacin. Leukotriene C4 also resulted in an average loss of 20% in plasma volume which, during the postinfusion period, perpetuated the low cardiac output state and thus provoked the release of angiotensin II. This vasoactive peptide sustained the elevation in systemic vascular resistance and the reduction in renal blood flow over a 70-minute postinfusion observation period. Consequently, glomerular filtration rate fell by approximately 50%. These angiotensin II-mediated effects were abolished by saralasin. Indomethacin prevented the leukotriene C4-induced loss of plasma volume and, thus, allowed for the significant recovery of cardiac output and renal blood flow during the post-infusion period, thereby preserving glomerular filtration rate. We conclude that leukotriene C4 exerts direct systemic and renal vasoconstrictor, as well as cardiodepressant effects, during the period of its infusion. By virtue of its vasopermeability enhancing effect, leukotriene C4 also results in an immediate loss of plasma volume, an effect which requires the presence of secondarily generated cyclooxygenase products and which perpetuates the hemodynamic abnormalities observed beyond the period of leukotriene C4 infusion.

Animals↗
PubMed1984

Role of angiotensin II in the altered renal function of congestive heart failure.

Glomerular and tubule functions were assessed by micropuncture in rats with extensive myocardial infarction produced by ligation of the left coronary artery 4 weeks prior to study. When compared to sham-operated control rats, rats with myocardial infarction involving 40 +/- 4% of the left ventricular circumference had lower mean arterial pressure (96 +/- 5 vs. 122 +/- 4 mm Hg, P less than 0.005), and higher left ventricular end-diastolic pressure (24 +/- 3 vs. 5 +/- 0 mm Hg, P less than 0.001). Renal cortical microcirculatory dynamics of rats with myocardial infarction were characterized by reduced glomerular plasma flow rate (75 +/- 8 vs. 165 +/- 17 nl/min, P less than 0.005), but a proportionately lesser decline in single nephron glomerular filtration rate (28.0 +/- 2.8 vs. 41.7 +/- 3.1 nl/min, P less than 0.025), accounting for the observed rise in single nephron filtration fraction (0.38 +/- 0.02 vs. 0.25 +/- 0.02, P less than 0.005). These renal hemodynamic alterations in myocardial-infarcted rats were accompanied by a striking elevation in efferent arteriolar resistance (3.03 +/- 0.31 vs. 0.95 +/- 0.16 X 10(10) dyn X sec X cm-5, P less than 0.001). In addition, fractional proximal fluid reabsorption, assessed by end-proximal tubule fluid-to-plasma inulin concentration ratio, was elevated (2.21 +/- 0.12 vs. 1.64 +/- 0.09, P less than 0.025). The intravenous infusion of teprotide, an angiotensin I-converting enzyme inhibitor, led to the return of glomerular plasma flow rate, single nephron filtration fraction, single nephron glomerular filtration rate, efferent arteriolar resistance, and fractional proximal fluid reabsorption in myocardial-infarcted rats to, or toward, the levels found in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1984

Hemodynamic basis for glomerular injury in rats with desoxycorticosterone-salt hypertension.

Micropuncture and/or morphologic studies were performed in seven groups of uninephrectomized (UNX) adult male Munich-Wistar rats. Control groups 1, 3, and 6 received standard (24% protein) chow and tap water. Groups 2, 4, and 5 received weekly injections of desoxycorticosterone pivilate (DOC) and 1% saline for drinking, groups 2 and 4 were fed standard chow, and Group 5 a diet containing 6% protein. Group 7 received DOC, salt, and standard chow for 3 wk followed by withdrawal of DOC and salt for an additional 6 wk. 10-14 d after UNX, groups 1 and 2 exhibited similar single nephron glomerular filtration rates (SNGFR) and initial glomerular plasma flow rates (QA). Group 2 had higher mean arterial pressure (AP) and glomerular capillary hydraulic pressure (PGC) than group 1. 3-4 wk after UNX, group 4 exhibited further elevations in AP and PGC as compared with groups 2 and 3. SNGFR and QA were similar in groups 3 and 4, but these average values were greater than typical for normal rats. Group 4 also demonstrated increased urinary protein excretion. Morphologic evaluation of glomeruli in groups 2 and 4 revealed mesangial expansion and focal intraglomerular hemorrhage whereas glomeruli of groups 1 and 3 were essentially normal. Values for AP and PGC in group 5 were not different than group 3 but significantly lower than group 4. QA and SNGFR were lower in group 5 (low protein) than in groups 3 and 4. Furthermore, proteinuria and glomerular structural lesions were abolished in group 5. Morphologic studies performed in groups 6 and 7 showed that early DOC-SALT lesions progress to focal glomerular sclerosis. These studies suggest that continued elevations in glomerular capillary flows and pressures predispose to glomerular injury in this model of systemic arterial hypertension.

Animals↗
PubMed1984

Adaptation of Na+-H+ exchange in renal microvillus membrane vesicles. Role of dietary protein and uninephrectomy.

The ablation of renal mass and institution of a high protein diet both lead to renal cortical hypertrophy and increased glomerular filtration rate (GFR). We studied Na+ transport in rat microvillus membrane vesicles isolated from uninephrectomized or sham operated rats fed 6% (low), 24% (standard), or 40% (high) protein diets. The feeding of high protein, as compared with low protein, was associated with a 50% increase in rates of pH-stimulated 22Na+ transport in isolated vesicles from sham and uninephrectomized animals. Values for the standard protein diet were intermediate to values for high and low protein. At each level of dietary protein intake, vesicular Na+ transport was greater in the uninephrectomized than in sham rats. The high protein diet was also associated with increased vesicular 22Na+ flux inhibitable by 1 mM amiloride. Increases in total and amiloride sensitive flux were also noted in the absence of a pH gradient. Conductive Na+ and H+ transport were not altered, nor were sodium-glucose and sodium-alanine cotransport. Kinetic studies revealed evidence for an increased Vmax of Na+-H+ exchange in uninephrectomized animals fed a 40 vs. a 6% protein diet whereas Km was unchanged. Supplements of NaHCO3 in the 40% protein diet, to adjust for an increased rate of net acid excretion, did not prevent the increased rates of Na+-H+ exchange. However, treatment with actinomycin D (0.12 mg/kg) prevented the increased Na+-H+ activity as well as the increased renal mass and GFR noted 24 h after unilateral nephrectomy. Na+-H+ exchange rate was closely correlated with GFR (r = 0.961; P less than 0.005) and renal mass (r = .986; P less than 0.001). These observations provide evidence for modification of the luminal membrane Na+-H+ exchanger in response to changes in dietary protein content and nephron number.

Animals↗