Amiloride-sensitive Na+-H+ exchange activity in brush border membrane vesicles isolated from rat proximal tubule was increased in metabolic acidosis. The enhancement of exchange activity required an intact adrenal gland or glucocorticoid supplements. Ammonium and phosphate excretions were increased during acidosis and these were also largely dependent on an intact adrenal gland or glucocorticoid supplements. Amiloride-insensitive Na' uptake and passive H+ permeability were not altered by acidosis or the glucocorticoid status of the animal. These findings are consistent with glucocorticoids having an important regulatory role in the kidney by orchestrating the proximal tubular adaptation to metabolic acidosis.The kidney responds to metabolic acidosis by increasing secretion of acid, phosphate, and ammonium and by enhancing reabsorption of bicarbonate (1). Acid secretory processes provide a mechanism for bicarbonate reabsorption, 80%o of which occurs in the proximal tubule (2). This nephron segment is the locus of the Na+-H' exchanger (3). The carrier, found in the brush border membrane, mediates the electroneutral antiport of Na+ for H+ (4-6). Amiloride, at relatively high concentrations (Ki = 0.05 mM), competitively inhibits exchange activity (7).Metabolic acidosis is also associated with increased levels of adrenal corticosteroids (8-10). Adrenalectomy decreases renal net excretion of titratable acids and ammonium (8,9) and hyperglucocorticoid states are concomitant with metabolic alkalosis (11). Glucocorticoids increase endogenous acid production, stimulate acid secretion, enhance ammonium production, and induce phosphaturia (12)(13)(14). The site of action of glucocorticoids in decreasing phosphate reabsorption is largely confined to the proximal tubule (15), where glucocorticoid receptors have been found (16). In addition, we have recently reported that the glucocorticoid dexamethasone, but not the mineralocorticoid aldosterone, increases amiloride-sensitive Na+-H+ exchange activity and selectivity decreases Na+ gradient-dependent phosphate uptake in proximal tubule brush border membrane vesicles (17).These findings raise the possibilities that metabolic acidosis induces changes in renal brush border Na+-H+ exchange activity and phosphate and ammonium excretion and, further, that glucocorticoids may have a role in mediating these effects. The present communication addresses these questions.METHODS AND MATERIALS Animals: Dexamethasone Administration and Acid-Base Status. Male Sprague-Dawley rats weighing 200-320 g were fed Purina rat chow pellets ad libitum and had 0.9% saline in their drinking water for 6-8 days. Acidotic rats were given, in addition, 1% NH4Cl in the water. The adrenals of adrenalectomized animals were removed under light ether anesthesia on day 1. Dexamethasone-treated animals were given two injections (30 ,ug/100 g of body weight) of dexamethasone in 0.9% saline, 24 and 16 hr prior to sacrifice. The glucocorticoid dose approximated that reported to lead to a large increase in total...

The tumorigenicity, migration, growth and invasiveness of certain tumor cells is stimulated by basement membranes. Here we have examined the effect of Matrigel, an extract of basement membrane proteins, on the behavior of several prostate cancer cell lines, testing their growth and invasiveness in vitro and in vivo. Cells of the Tsu-prI line were more invasive than PC-3, Du-145, or LNCaP cells. Peptide inhibitors implicated laminin in the migration and invasion of these cells. When these cells were suspended in Matrigel and injected into nude mice, their growth was greatly enhanced, since large tumors formed in athymic nude mice whereas virtually no tumors were observed in the absence of Matrigel. The growth of a slowly growing line, LNCaP, was increased by exogenous basic fibroblast growth factor when injected with Matrigel. A laminin cell adhesion peptide, YIGSR, was a potent inhibitor of Matrigel-stimulated tumor growth implicating cell-laminin interactions in this process. These results suggest that tumor growth of prostate adenocarcinoma cells may be dependent both on cellular growth factors and on cell-matrix interactions mediated by laminin which facilitate the development of transplanted tumors in nude mice.

Na+-H+ exchange activity in renal brush border membrane vesicles isolated from hyperthyroid rats was increased. When examined as a function of [Na+], treatment altered the initial rate of Na+ uptake by increasing Vm (hyperthyroid, 18.9 +/- 1.1 nmol Na+ X mg-1 X 2 sec-1; normal, 8.9 +/- 0.3 nmol Na+ X mg-1 X 2 sec-1), and not the apparent affinity KNa+ (hyperthyroid, 7.3 +/- 1.7 mM; normal, 6.5 +/- 0.9 mM). When examined as a function of [H+] and at a subsaturating [Na+] (1 mM), hyperthyroidism resulted in the proportional increase in Na+ uptake at every intravesicular pH measured. A positive cooperative effect on Na+ uptake was found with increased intravesicular acidity in vesicles from both normal and hyperthyroid rats. When the data were analyzed by the Hill equation, it was found that hyperthyroidism did not change the n (hyperthyroid, 1.2 +/- 0.06; normal, 1.2 +/- 0.07) or the [H+]0.5 (hyperthyroid, 0.39 +/- 0.08 microM; normal, 0.44 +/- 0.07 microM) but increased the apparent Vm (hyperthyroid, 1.68 +/- 0.14 nmol Na+ X mg-1 X 2 sec-1; normal 0.96 +/- 0.10 nmol Na+ X mg-1 X 2 sec-1). The uptake of Na+ in exchange for H+ in membrane vesicles from normal and hyperthyroid animals was not influenced by membrane potential. H+ translocation or debinding was rate limiting for Na+-H+ exchange since Na+-Na+ exchange activity was greater than Na+-H+ exchange activity. Hyperthyroidism caused a proportional increase and hypothyroidism caused a proportional decrease in Na+-Na+ and Na+-H+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS)