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Biomedical subjects

B M Brenner

Publications and source records attributed to B M Brenner.

At least 181 records · Page 10Linked to original sources
PubMed1987

Uninephrectomy and dietary protein affect fluid absorption in rabbit proximal straight tubules.

To further delineate the mechanisms involved in the renal compensatory response to renal mass ablation, we evaluated the interactions of protein intake and uninephrectomy on total, active, and passive fluid absorption (Jv) in the in vitro perfused superficial proximal straight tubule (SFPST) isolated from sham-operated or uninephrectomized rabbits pair fed 7, 14, or 45% protein diets. In all protein groups, we observed significant increases in Jv and in cell height from SFPST segments obtained from remnant renal tissue harvested 3 wk post-uninephrectomy when compared with sham-operated controls. Uninephrectomy also led to compensatory hypertrophy of whole-kidney mass and to elevations in inulin clearances. Increased protein intake consistently enhanced these renal and SFPST structural and functional changes, whereas protein restriction limited compensatory responses. The changes in Jv following uninephrectomy were attributable to increases in the active, but not the passive, component of Jv in all protein groups. Moreover, the active component of Jv could be modified by altering dietary protein intake. Single kidney inulin clearances were correlated with the changes in total Jv with ultrafiltrate perfusate (r = 0.88; P less than 0.025), with artificial perfusate (r = 0.95; P less than 0.01), the active component of Jv (r = 0.96; P less than 0.005), SFPST cell height (r = 0.94; P less than 0.01), and whole-kidney weight (r = 0.99; P less than 0.005). These results indicate that hypertrophy of renal structure and augmentation of function following uninephrectomy and increased dietary protein are also observed in single rabbit SFPST segments perfused in vitro; that the hypertrophic responses following uninephrectomy can be enhanced or reduced by increases or decreases in protein intake, respectively; and that these changes are paralleled by changes in glomerular filtration rate.

Absorption↗
PubMed1987

Effects of leukotriene D4 on glomerular dynamics in the rat.

Glomerular micropuncture studies were performed in euvolemic, anesthetized, adult, male Munich-Wistar rats to evaluate the glomerular microcirculatory actions of leukotriene D4 (LTD4). In preliminary experiments, intrarenal arterial administration of LTD4 (1 microgram X kg-1 X min-1) was found to cause a rise in mean systemic arterial pressure, a loss of plasma volume, and a fall in renal blood flow, effects identical to those previously reported for LTC4. To assess the local glomerular actions of LTD4 independently of these systemic effects, glomerular microcirculatory dynamics were assessed during LTD4 infusion while constancy of renal perfusion pressure and plasma volume were maintained by partial aortic constriction and isoncotic plasma infusion, respectively. To ascertain the LTD4 actions that are independent of angiotensin II, saralasin (5 micrograms X kg-1 X min-1 iv) was also given throughout the study. LTD4 caused a significant increase in efferent arteriolar resistance in association with a fall in glomerular plasma flow rate (QA) and a rise in glomerular capillary hydraulic pressure. Despite the latter, single-nephron filtration rate fell due to combined reductions in QA and the glomerular ultrafiltration coefficient. These local glomerular constrictor actions of LTD4 support the possibility that this eicosanoid might play an important intermediary role in the functional impairment accompanying some forms of inflammatory injury.

Animals↗
PubMed1987

Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration.

Infusion of atrial natriuretic peptide (ANP) increases the glomerular filtration rate (GFR), and ANP is released from cardiac myocytes in response to extracellular fluid volume expansion. Since diabetes mellitus is associated with glomerular hyperfiltration and volume expansion, we investigated the relationship between ANP and GFR in diabetic rats given insulin to achieve stable moderate hyperglycemia or normoglycemia. At 2 wk after induction of diabetes, moderately hyperglycemic diabetic rats exhibited elevations of plasma ANP levels averaging 281 +/- 28 pg/ml vs. 158 +/- 15 pg/ml in normoglycemic diabetic rats. In hyperglycemic rats, the GFR was also elevated on average to 2.24 +/- 0.28 ml/min as compared with 1.71 +/- 0.13 ml/min in normoglycemic diabetic rats. To test further the relationship between ANP and GFR in diabetes, moderately hyperglycemic diabetic rats were infused either with a specific ANP antiserum or with nonimmune serum. The infusion of specific ANP antiserum uniformly reduced the GFR on average from 2.38 +/- 0.1 ml/min to 1.60 +/- 0.1 ml/min, whereas the infusion of nonimmune serum was without effect. It is concluded that elevated endogenous ANP levels contribute to the hyperfiltration observed in early diabetes in the rat.

Animals↗
PubMed1987

Chronic glucocorticoid therapy amplifies glomerular injury in rats with renal ablation.

Functional and/or structural measurements were performed in eight groups of Munich-Wistar rats after five-sixths nephrectomy. Groups 1 and 5 received no therapy. Groups 2 and 6 received daily doses of methylprednisolone (MP). Groups 3 and 7 received MP plus the angiotensin I converting enzyme inhibitor (CEI), benzazepril. Groups 4 and 8 received CEI alone. Groups 1 through 4 underwent micropuncture study 2 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate due to glomerular capillary hyperperfusion and hypertension. Administration of MP in group 2 resulted in comparable systemic hypertension, with further elevation of the single nephron glomerular filtration rate due to even higher values for glomerular perfusion and hydraulic pressure. Concurrent treatment with CEI in groups 3 and 4 controlled systemic and glomerular hypertension despite equivalent renal ablation and, in group 3, comparable doses of MP. Groups 5 through 8 were followed for 12 wk. Untreated group 1 rats demonstrated continued systemic hypertension, progressive proteinuria, and eventual glomerular sclerosis. Addition of MP in group 6 dramatically accelerated the development of proteinuria and glomerular sclerosis, while CEI (groups 7 and 8) afforded striking protection against disease progression. Thus, potent vasodilator glucocorticoids may amplify hemodynamically mediated glomerular injury, whereas control of systemic and glomerular hypertension prevents this undesirable consequence of chronic steroid therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Atrial natriuretic peptide and the kidney.

Studies addressing the mechanisms of atrial natriuretic peptide (ANP) action within the kidney are reviewed. The magnitude of the natriuretic response to ANP initially suggested inhibition of renal sodium transport. It now appears, however, that the renal response to ANP is largely dependent on ANP-induced alterations in renal hemodynamics. At the glomerulus, ANP-induced afferent arteriolar dilatation and efferent arteriolar constriction produce a rise in the glomerular capillary hydraulic pressure and thus an increase in the filtration fraction and glomerular filtration rate. Furthermore, angiotensin II-induced increments in renal perfusion pressure markedly augment ANP-induced NaCl excretion, whereas increments in peritubular oncotic pressure or reductions in renal perfusion pressure nearly abolish this natriuretic effect, thereby suggesting that changes in the peritubular physical factors, which govern tubule fluid reabsorption, are required to elicit the natriuretic action of ANP. In addition, increments in papillary vasa recta hydraulic pressures during ANP infusion argue for an important influence of ANP on fluid exchange in the renal papilla. There also is recent evidence to suggest that ANP directly inhibits papillary collecting duct NaCl reabsorption. This action of ANP is thought to contribute to the enhanced renal excretion of sodium-rich urine in response to ANP. Finally, in two models of chronic extracellular volume expansion, namely, mineralocorticoid excess and a reduction in nephron number with a high sodium intake, endogenous plasma ANP levels increased significantly above control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Therapeutic implications of converting-enzyme inhibitors in renal disease.

Micropuncture and morphological studies were performed in three protocols assessing the renal hemodynamic and structural effects of angiotensin I-converting enzyme inhibitors (CEIs) in the progression of glomerular injury. In protocol I, rats were subjected to 5/6 renal ablation and received no therapy, enalapril (CEI), or triple-drug therapy (TRX) for 12 weeks. Control of systemic and glomerular hypertension with CEI resulted in prevention of glomerular capillary hypertension and protection against glomerular injury. Despite equivalent control of systemic BP, failure of TRX to control glomerular hypertension was associated with no protection against eventual proteinuria and glomerular sclerosis, values for these indexes being as abnormal as in rats receiving no therapy. In protocol II, rats were again subjected to 5/6 renal ablation and followed for 18 weeks. Early institution of CEI soon after ablation again prevented systemic and glomerular hypertension and largely limited glomerular injury. In a third group, enalapril therapy was delayed for 8 weeks after ablation until hypertension and proteinuria were established. Late institution of CEI resulted in prompt reduction in systemic and glomerular capillary hypertension and stabilization of glomerular disease. In protocol III, CEI was administered to normotensive, moderately hyperglycemic diabetic rats. A modest, 20-mm Hg reduction in systemic arterial pressure was associated with the normalization of glomerular capillary pressure and a striking reduction in the development of albuminuria and glomerular injury. These studies suggest that CEI effectively prevent glomerular capillary hypertension and thereby afford protection against glomerular injury in diverse models of progressive renal disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Effects of aging on the renal glomerulus.

The biologic price of aging includes progressive deterioration of renal function and structure. After the age of 30, glomerular filtration and renal blood flow rates decline in a linear fashion, so that values in octagenarians are only half to two thirds those measured in young adults. Renal mass similarly declines, and the incidence of sclerotic glomeruli increases with advancing age. Accordingly, the aging kidney is at high risk of eventual failure when functioning nephron number is further reduced by acquired renal disease. Recent evidence suggests that limitation of dietary protein intake delays the development of age- and disease-related glomerular sclerosis in experimental animals, and that dietary protein restriction may postpone end-stage renal disease in patients with progressive renal insufficiency.

Adaptation, Physiological↗
PubMed1986

Pathogenesis of diabetic microangiopathy. The hemodynamic view.

Multiple factors, including altered levels of vasoactive substances, altered vasomotor responsiveness, chronic plasma volume expansion, and tissue hypoxia, contribute to a state of generalized microvascular vasodilatation in early insulin-dependent diabetes mellitus. This vasodilatation, with the consequent elevation in capillary pressures and flows, may be the initiating mechanism leading to both renal and extrarenal diabetic microangiopathy. Sustained hemodynamic actions on the microvasculature, besides directly injuring the capillary wall, promote increased permeability to macromolecules and increased capillary wall proliferation, with consequent thickening of basement membranes and luminal narrowing. These changes eventuate in complete microvascular obstruction and further vasodilatation of less damaged capillaries, thereby ensuring their eventual destruction. The ensuing complications depend on the nature of the surrounding tissue, ranging from reduction of functional reserve, as seen in skeletal muscle, to the devastating functional consequences observed in organs with endarterial circulation such as the kidney and retina.

Angiotensin II↗
PubMed1986

Roles for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure.

Bolus i.v. administration of 100 micrograms/kg of E. Coli lipopolysaccharide endotoxin (LPS) to adult male Munich-Wistar rats (N = 18) resulted in a progressive fall in RBF and GFR from 6.9 +/- 0.2 SE and 1.1 +/- 0.05 ml/min to minimal values at 50 minutes of 3.8 +/- 0.4 and 0.32 +/- 0.08 (P less than 0.05), respectively, without a fall in mean arterial pressure. At 50 minutes, renal cortical generation rates of PGE2 (1075 +/- 108 pg/mg tissue), 6 keto PGF1 alpha (221 +/- 41 pg/mg), and TxB2 (106 +/- 12 pg/mg) were significantly higher than those of vehicle-treated control rats (N = 10, PGE2 = 466 +/- 107, 6 keto PGF1 alpha = 94 +/- 3, and TxB2 = 35 +/- 3 pg/mg), and morphologic examination revealed normal histology with notable absence of leukocytes and platelets. Pretreatment of a third group of nine rats with TxA2 synthetase inhibitor UK-37.248 (dazoxiben, 10 mg/kg) selectively abolished the LPS-induced rise in TxB2 (29 +/- 3 pg/mg), but not PGE2 (837 +/- 62 pg/mg) or 6 keto PGF1 alpha (179 +/- 5 pg/mg), prevented the fall in RBF at 50 minutes (6.3 +/- 0.4 ml/min), and allowed for significant preservation of GFR (0.67 +/- 0.08 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1986

Chronic effects of dietary protein in the rat with intact and reduced renal mass.

The chronic effects of dietary protein on renal structure and function were studied in rats with normal and reduced renal mass. Control rats with two kidneys were compared with unilaterally nephrectomized rats, and with one and one-third nephrectomized rats obtained by unilateral nephrectomy and infarction of one-third of the remaining kidney. Rats at each level of renal mass were maintained on chow containing either 6% or 40% protein content. Separate cohorts of rats were studied four and eight months after ablation and institution of these dietary regimens. At both time intervals and at all levels of renal mass, rats fed the high protein diet had higher average values for GFR than comparable animals fed the low protein chow. Within each of the dietary regimens the animals with loss of renal mass developed greater prevalences of sclerotic glomeruli by eight months. Furthermore, at each level of initial renal mass, rats eating the high protein diet had a greater prevalence of sclerotic glomeruli than those on the low protein diet. Similarly, rats on the high protein diet had greater rates of protein excretion than those on the low protein diet at each degree of ablation. The prevalence of sclerosed glomeruli increased between four and eight months in each group. Thus, the extent of renal injury as manifested by proteinuria and glomerular sclerosis was directly related to the degree of initial loss of renal mass, and dietary protein restriction retarded these manifestations of injury across a wide range of initial renal mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effect of colloid volume expansion on glomerular barrier size-selectivity in humans.

Colloid volume expansion magnifies proteinuria in subjects with the nephrotic syndrome. To elucidate this phenomenon, we performed differential solute clearances prior to and following infusion of hyperoncotic albumin in 21 nephrotic subjects and seven healthy controls. Urinary excretion rate and fractional clearance of albumin (radius = 36 A) and immunoglobulin G (radius = 55 A) increased significantly in nephrotic subjects. However, urinary albumin excretion rate was unchanged in controls. The fractional clearances of dextrans of broad size distribution (radii = 28 to 58 A) were markedly altered in both groups following albumin infusion. A heteroporous model which depicts the major portion of the glomerular capillary wall as an isoporous membrane (pore radius approximately 55 A) and the minor portion as a non-discriminatory shunt, revealed the latter to be much more prominent in nephrotic subjects than in controls, and to be enlarged further following albumin infusion. By contrast no increase in pore size of the non-shunt pathway occurred in either group. We infer that enhancement of a pre-existing defect of glomerular size-selectivity in nephrotic subjects accounts, in large part, for exaggerated proteinuria in the colloid volume-expanded state. Increases in glomerular perfusion rate and pressure associated with plasma hypervolemia may mediate this alteration in glomerular membrane-pore structure.

Capillary Permeability↗
PubMed1986

Purification and characterization of the amiloride-sensitive sodium channel from A6 cultured cells and bovine renal papilla.

The amiloride-binding Na+ channel protein of high electrical resistance epithelia was solubilized and purified from cultured A6 toad kidney cells and bovine renal papilla. Purification was assessed by enrichment in [3H]methylbromoamiloride specific binding. Chromatography of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS)-solubilized plasma membrane vesicles on agarose-immobilized wheat-germ agglutinin provided a 130-fold enrichment of the amiloride-binding component compared to the cell homogenate. Further purification was achieved by either amiloride-affinity chromatography or size-exclusion HPLC. When the HPLC and amiloride affinity-purified material was injected into a second higher molecular weight exclusion HPLC column, only a single peak with Mr 800,000 was found. Further HPLC separation of the Mr 800,000 material at low ionic strength resolved two peaks with apparent Mrs 800,000 and 700,000. Only the 700-kDa component displayed specific [3H]methylbromoamiloride binding activity. The final binding specific activity achieved was 1300 pmol/mg of protein, corresponding to 91% homogeneity of the protein.

Amiloride↗
PubMed1986

Role of the kidney in congestive heart failure.

The changes in renal function observed in congestive heart failure include altered pressures and flows and increased reabsorption of sodium and water leading to expanded extracellular fluid volume. These renal effects are mediated by a variety of volume and pressure sensors that stimulate various effectors which act on the kidney. The role of these sensors and effectors, the relationship between left ventricular function (LVF) and urinary sodium excretion (UNaV) and the role of angiotensin II in mediating the renal hemodynamic changes are reviewed. Rats with experimentally induced myocardial infarction (MI) were studied 3 weeks after infarction. Although UNaV decreased as LVF worsened, the decrease in UNaV was evident even in rats with MI and minimal LVF impairment. Infusion of teprotide (an inhibitor of angiotensin I converting enzyme) returned the hemodynamic parameters to or toward values seen in rats without MI, thereby documenting an important role for angiotensin II in congestive heart failure.

Angiotensin II↗