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Biomedical subjects

B M Brenner

Publications and source records attributed to B M Brenner.

At least 145 records · Page 8Linked to original sources
PubMed1990

Leukotrienes stimulate neutrophil adhesion to mesangial cells: modulation with lipoxins.

We have examined polymorphonuclear neutrophil (PMN) adhesion to mesangial cells (MC) in vitro and have assessed the actions of lipoxygenase (LO) products in this process. On exposure to either leukotriene B4 (LTB4), or leukotriene D4 (LTD4), 111In-labeled PMNs adhere to monolayers of cultured MC. These actions were rapid in onset (less than 5 min) and dependent upon leukotriene concentration (10(-9) to 10(-6) M) and the presence of divalent cations. Adhesion was sustained (0-30 min), and neither LTB4 nor LTD4 was metabolized to inactive products during PMN-MC interaction, as determined by their recovery after reverse-phase high-performance liquid chromatography. LTB4 was a PMN-directed stimulus, whereas LTD4 appeared to act on MC. A monoclonal antibody (TS 1/18) against the CD18 component of the PMN CD18/CD11 adhesion complex inhibited the LTB4-induced response, indicating involvement of this PMN glycoprotein in the adhesion process. In contrast, this antibody did not affect LTD4-induced adhesion, suggesting that this response was mediated by other adhesion epitopes. When added alone, neither lipoxin A4 (LXA4) nor lipoxin B4 (LXB4) provoked PMN adhesion to MC. In contrast, LXA4 and LXB4 at equimolar concentrations attenuated the LTD4- but not LTB4-induced response. Together, these results provide further evidence that LO-derived eicosanoids may constitute important early signals that regulate PMN-MC interaction in glomerular inflammation.

Cell Adhesion↗
PubMed1990

Determinants of epithelial differentiation during early nephrogenesis.

Organogenesis from undifferentiated progenitor cells and initiation of a society's new journal are developmental processes which share common elements. Both initially require a potent inducing stimulus followed in relatively rapid sequence by the appearance of organ-specific differentiation markers. These events are prerequisites to subsequent proliferation and maturation. Insofar as many postnatal forms of renal disease (e.g., hereditary glomerulopathies, infantile and adult forms of polycystic kidney disease, congenital dysplasias) owe their origins ultimately to disordered nephrogenesis, it is my belief that research in this area of nephrology should expand. It is further hoped that JASN will adopt this particular differentiation marker and serve as a forum for reporting the much-needed new knowledge to be gained. To "induce" the Journal's activity in this area I have summarized current knowledge and suggest directions in need of further investigation.

Animals↗
PubMed1989

Identification and characterization of endothelin binding sites in rat renal papillary and glomerular membranes.

The present study was designed to identify and characterize specific endothelin binding sites in membranes of rat renal papillae and glomeruli which appear to be target tissues for this new peptide hormone. Saturation binding studies indicate that the sites have a high and uniform affinity. The dissociation constants averaged 662 +/- 151 and 1309 +/- 123 pM and the receptor densities 7666 +/- 920 and 5831 +/- 348 fmol/mg protein for papillary and glomerular membranes, respectively. Endothelin 1, endothelin 3 and sarafotoxin all inhibited [125I]-endothelin binding with IC50's in the 100-300 pM range, whereas unrelated peptides, namely angiotensin II, atrial natriuretic peptide, and platelet-derived growth factor failed to compete for [125I]-endothelin binding. Deletion of the carboxyterminal tryptophan in endothelin 1 reduced its affinity for glomerular binding sites by 2 orders of magnitude. Specific endothelin binding to these membranes was maximal at pH 4 and was markedly inhibited as the pH was raised above 8. When [125I]-endothelin is covalently linked to glomerular membrane binding sites, SDS-PAGE of these solubilized membranes followed by autoradiography reveals a predominant specifically labeled band of 45 kDa. Whether this band represents a subunit of the endothelin receptor(s), the receptor proper, or an intracellular endothelin binding protein remains to be determined.

Animals↗
PubMed1989

Endothelin action on vascular smooth muscle involves inositol trisphosphate and calcium mobilization.

Cultured endothelial cells release a potent vasoconstrictor peptide, endothelin. Cumulative addition of synthetic endothelin to isolated rabbit aortic rings elicited a concentration-dependent increase in contractile tension which was endothelium-independent. In cultured rabbit vascular smooth muscle cells loaded with the fluorescent dye fura 2, endothelin induced a concentration-dependent increase in [Ca2+]i over the range of 0.01 to 100 nM. Moreover, in the absence of extracellular Ca2+, endothelin could still induce an increase in [Ca2+]i. In addition, endothelin stimulated 45Ca2+ efflux from preloaded vascular smooth muscle cells in the presence and absence of extracellular Ca2+, as well as stimulating 45Ca2+ influx in a concentration-dependent manner. Measurement of inositol phosphates in [3H]-myoinositol-labelled vascular vascular trisphosphate. Unlabelled endothelin inhibited (125I)-endothelin binding to cultured rabbit vascular smooth muscle cells in a concentration-dependent manner. Binding was not inhibited by other vasoactive hormones or calcium channel ligands, suggesting cell surface receptors specific for endothelin. We conclude that one of the initial membrane events in the action of endothelin is to induce phospholipase C-stimulated PIP2 hydrolysis and that this signalling mechanism is initiated by endothelin/receptor interaction at the plasma membrane.

Animals↗
PubMed1989

Short and long term effects of antihypertensive therapy in the diabetic rat.

To compare the impact of differing antihypertensive regimens on the development of renal injury, studies were performed in three groups of moderately hyperglycemic diabetic rats, and one group of non-diabetic control (C) rats. One diabetic group (DM) received no therapy except insulin. The remaining diabetic groups received insulin and either the angiotensin I converting enzyme inhibitor captopril (CAP), or triple therapy (TRX) with reserpine, hydralazine and hydrochlorothiazide. CAP and TRX modestly and comparably lowered blood pressure. At 6 to 10 weeks, DM rats exhibited elevation of the single nephron glomerular filtration rate (SNGFR), due to elevations of the glomerular capillary plasma flow rate (QA) and the glomerular capillary hydraulic pressure (PGC). In both DM/CAP and DM/TRX rats, blood pressure reduction was associated with selective normalization of PGC, without change in SNGFR or QA. In long-term (70 weeks) studies, DM rats exhibited progressive albuminuria and marked glomerular sclerosis. CAP limited albuminuria and injury to values even lower than those in C rats, whereas TRX served only to delay, but not to prevent, the increase in albuminuria. TRX reduced glomerular sclerosis, but was less effective than CAP. At 70 weeks, CAP and TRX still reduced systemic blood pressure; PGC remained at normal levels with CAP but was no longer controlled with TRX. These results confirm the clinical observation that antihypertensive therapy slows diabetic glomerulopathy, but also suggest that CAP affords superior long-term protection as compared to the other antihypertensive drug regimen studied.

Animals↗
PubMed1989

Endothelin, a peptide inhibitor of Na(+)-K(+)-ATPase in intact renaltubular epithelial cells.

Endothelin, a potent vasoconstrictor released by vascular endothelial cells, can induce natriuresis in vivo. These studies examined the regulation of Na+ transport by endothelin in suspensions of rabbit proximal tubule (PT) and inner medullary collecting duct (IMCD) cells. Endothelin reduced oxygen consumption (QO2) by 18 +/- 1% in IMCD cells but did not alter QO2 in PT cells. In IMCD cells, endothelin inhibited QO2 half maximally at approximately 5 x 10(-12) M. Several lines of evidence indicate that endothelin reduces QO2 by inhibiting the Na(+)-K(+)-ATPase. 1) Endothelin gave no further inhibition of QO2 after ouabain and blunted the stimulatory effect of amphotericin B on QO2 (+29 +/- 4% in absence of endothelin, 0 +/- 5% in presence of endothelin; n = 6 preparations, P less than 0.001). 2) Endothelin inhibited ouabain-sensitive 86Rb+ uptake by 46.6 +/- 8.6% at 10 s and by 35.4 +/- 5.3% at 30 s without altering uptake at 60 min. 3) Addition of endothelin to IMCD cells induced a net K+ efflux with an initial rate of 32.2 +/- 4.8 nmol.min-1.mg protein-1, consistent with inhibition of the Na(+)-K(+)-ATPase. In contrast to the response observed in intact cells, in permeabilized IMCD cells endothelin did not inhibit ouabain-sensitive ATPase. Several observations indicated that prostaglandin E2 (PGE2) mediates endothelin inhibition of Na(+)-K(+)-ATPase activity. 1) The response to endothelin was blocked by ibuprofen in assays of QO2, net K+ flux, and 86Rb+ uptake. 2) Endothelin and PGE2 gave equivalent, nonadditive inhibition of ouabain-sensitive 86Rb+ uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Characteristics of ANP-sensitive guanylate cyclase in inner medullary collecting duct cells.

Our previous characterization of equilibrium binding kinetics of atrial natriuretic peptide (ANP) to the surface of inner medullary collecting duct (IMCD) cells suggested the existence of a single class of high-affinity receptors, functionally coupled to increases in cellular guanosine 3',5'-cyclic monophosphate (cGMP). We have now sought to understand the mode of regulation of this signal transduction system by studying the particulate guanylate cyclase (PGC) enzyme from these cells. PGC activity with and without ANP in membranes, made by homogenization and high-speed centrifugation of suspensions of IMCD cells, was linear up to 5 min and was stimulated by ANP [143 +/- 21 (ANP) vs. 38 +/- 7 (control) pmol/mg protein, n = 3, P less than 0.02]. Vmax increased more than threefold with ANP [130 +/- 19 (ANP) vs. 35 +/- 4 (control) pmol.mg protein-1.min-1, n = 4, P less than 0.005] without significant change in the Km [0.68 +/- 0.17 (ANP) vs. 0.55 +/- 0.08 (control) mM] of the enzyme. Half-maximal stimulation of guanylate cyclase activity occurred at 5 x 10(-10) M ANP, a concentration consistent with our binding data, and with physiological effect. PGC required divalent cations for basal activity and for ANP-stimulated activity; Mg2+ and Mn2+ were most potent in this respect, and Ca2+ was without effect. Both basal and stimulated PGC activities were inhibited in response to changes in the NaCl, but not urea concentration of the assay system. We conclude that binding to the single 120-130 kDa ANP receptor in IMCD cells results in stimulation of PGC by increasing its Vmax and thereby elevating intracellular cGMP, the likely mediator of ANP action in these cells.

Animals↗
PubMed1989

Endothelin: a potent renal and systemic vasoconstrictor peptide.

Endothelin is an endothelial cell-derived peptide recently shown to possess potent vasoconstrictor properties. Bolus intravenous injections of endothelin (5-450 pmol) into anesthetized Munich-Wistar rats induced a marked pressor effect, the magnitude and duration of which were dose dependent. Maximal systemic and renal responses occurred within 20 min and persisted for greater than 90 min in the higher dose range. In response to bolus dosages of 25 pmol or greater, renal plasma flow fell proportionately more than glomerular filtration rate, resulting in an increase in filtration fraction. In micropuncture studies of rats given continuous intravenous infusions of endothelin (0.63 pmol/min), the peptide caused a proportionately greater elevation of efferent than afferent arteriolar resistance, with a marked elevation of glomerular capillary hydraulic pressure and a lower glomerular capillary ultrafiltration coefficient. Endothelin was modestly natriuretic when systemic pressure rose and renal function was not severely impaired. This potent renal and systemic vasoconstrictor may play an important role in glomerular injury and in the pathophysiology of a variety of clinical microvasculopathies.

Animals↗
PubMed1989

Enkephalinase inhibition increases plasma atrial natriuretic peptide levels, glomerular filtration rate, and urinary sodium excretion in rats with reduced renal mass.

To investigate the in vivo effects of inhibition of endopeptidase 24.11, an enkephalinase enzyme shown to be involved in atrial natriuretic peptide (ANP) breakdown in vitro, we infused phosphoramidon, a specific inhibitor of endopeptidase 24.11, into rats with reduced renal mass (and chronic extracellular volume expansion) and into normal rats. Relative to baseline values in rats with remnant kidneys, phosphoramidon led to elevations of plasma ANP levels and concomitant increases in urinary sodium excretion, fractional excretion of sodium, glomerular filtration rate, filtration fraction, and urinary cyclic GMP excretion. Similar changes in renal function and urinary cyclic GMP excretion were obtained with thiorphan, another endopeptidase 24.11 inhibitor. These enhanced ANP levels and renal actions were not observed with phosphoramidon in normal rats. These results show that plasma ANP levels can be modulated in rats with reduced renal mass by inhibition of endopeptidase 24.11.

Animals↗
PubMed1989

Hyperlipidemia and glomerular sclerosis: an alternative viewpoint.

Clinical and experimental observations suggest an association between hypercholesterolemia and progressive glomerular injury. In the main, most investigators have assumed that hypercholesterolemia induces an atherosclerotic process in the renal microvasculature analogous to that well recognized in larger vessels. The evidence for this line of reasoning is well described in other papers in this symposium. It is our belief that hypercholesterolemia may also lead to glomerular injury by hemodynamic mechanisms. In support of this latter view, diet-induced hypercholesterolemia often raises blood pressure in experimental animals and markedly impairs endothelial cell-dependent vascular relaxation in vitro. A high cholesterol diet also increases renal vascular resistance and contributes to glomerular capillary hypertension, a hemodynamic maladaptation known to cause glomerular sclerosis. In addition, hypercholesterolemia results in hyperviscosity, a rheologic abnormality leading to increased efferent arteriolar resistance and glomerular hypertension. The similar glomerular hemodynamic responses to two hyperviscosity states, elevated hematocrit and hypercholesterolemia, implicate efferent arteriolar hyperviscosity as a potential mechanism of injury common to hyperviscosity states. It therefore seems likely that as in atherosclerosis, multiple risk factors act synergistically to initiate glomerular structural injury. Specifically, we suggest that hypercholesterolemia and glomerular hypertension act synergistically to initiate structural injury. Although modification of either risk factor may limit injury, it seems likely that therapy targeted to each of multiple risk factors may afford superior protection.

Animals↗