Secretion and degradation of parathormone as a function of intracellular maturation of hormone pools. Modulation by calcium and dibutyryl cyclic AMP.

The biosynthesis, processing, and secretion of parthormone and the effect of calcium on these processes were measured in dispersed porcine parthyroid cells incubated with [(35)S]methionine. Proparathormone was detected at 10 min, the earliest time measured, and was rapidly and apparently quantitatively converted to parathormone. The half-life of the prohomormone pool was 15 min. Secretion of parathormone was detected by 20 min. In pulse-chase experiments there was a period between 20 and 40 min during which the wave of newly-synthesized parathormone was secreted. After 40 min during little additional radioactive hormone was secreted, but dibutyryl cyclic AMP, an agent that can mobilize stored parathormone, when added to the incubation mixtures enhanced radioactive parathormone secretion but only after 60 min, although it increased net hormone secretion as determined by radioimmunoassay to the same extent at all times studied. When the ionized calcium concentration of the medium was lowered, more radioactive hormone was secreted at all times but the effect was greatest on that hormone that was synthesized less than 60 min previously ; however, net hormone secretion in contrast to radioactive hormone was enhanced equally at all intervals. These data could mean that the refractoriness to secretion of parathormone 40-60 min of age was related to maturation of secretory container preparatory to storage. Low calcium (0.5 mM) stimulated hormone secretion up to fivefold compared to high calcium (3.0 mM) but did not affect synthesis of parathormone or proparathormne or conversion of the latter to hormone. During processing at least 70 percent of the intracellular parathormone was lost, presumably through proteolysis and this degradation was greater at high calcium. These data have been interpreted in light of the concept that two secretable pools of parathormone exist within the parathyroid.

Regulation of secretion of parathormone and secretory protein-I from separate intracellular pools by calcium, dibutyryl cyclic AMP, and (1)-isoproterenol.

Dispersed porcine parathyroid cells were incubated at calcium concentrations between 0.5 and 3.0 mM in the presence of 3H- or 14C-amino acids to label newly synthesized parathormone. Up to four times more hormone was secreted at the lower calcium concentration but its specific radioactivity, from 30 to 50 times that of the intracellular pool, did not change. Dibutyrl cyclic AMP doubled immunoactive parathormone secretion at each calcium concentration, but there was no increase in secretion of radioactive hormone if labeled amino acids and secretagogue were added simultaneously. Similarly, when the intracellular pool of parathormone was prelabeled with 3H-amino acids and then the cells were incubated in 14C-amino acids and dibutyryl cyclic AMP, the entire increase in hormone secreted was derived from the prelabeled pool. (1)-isoproterenol increased intracellular cyclic AMP and acted on hormone secretion in a manner indistinguishable from dibutyryl cyclic AMP. In similar double-label experiments dibutyryl cyclic AMP preferentially enhanced secretion of secretory protein-I, a calcium-regulated protein of the parathyroid of unknown function. Calcium, alone, inhibited the intracellular level of cyclic AMP in a concentration-dependent fashion. These data are consistent with the existence in the parathyroid cell preparation of two hormone and secretory protein pools that may be individually recruitable--one consisting of most recently synthesized protein, the other consisting of older "storage" protein. The data do not allow one to decide whether the two pools coexist within individual cells or whether, instead, they exist in separate cells of the dispersed gland preparation.

Cyclic AMP-dependent protein phosphorylation and dephosphorylation alter phosphate transport in canine renal brush border vesicles.

We have previously demonstrated that the cAMP-dependent phosphorylation of two or more proteins (bands IX and V) in membrane vesicles isolated from the renal brush border from kidneys of dogs, was associated with decreased Na+-dependent Pi transport. In the present studies a specific dephosphorylation of band IX was demonstrated in brush border vesicles incubated in the absence of F- which had been used in previous studies to inhibit phosphoprotein phosphatase activity. Dephosphorylation of band IX was 80% complete after 5 min of incubation at which time inhibition of Pi transport in membrane vesicles which had been phosphorylated in the presence of cAMP could no longer be demonstrated. Dephosphorylation of band IX was no different in vesicles from kidneys originating from parathyroidectomized dogs prior to or following the administration of parathyroid hormone in vivo and normal dogs. We conclude that the cAMP-dependent phosphorylation of brush border membrane proteins may mediate a phosphaturic effect of the hormone. Parathyroid hormone-induced phosphaturia may be terminated through the action of a specific membrane phosphoprotein-phosphatase.

NAD+-induced inhibition of phosphate transport in canine renal brush-border membranes. Mediation through a process other than or in addition to NAD+ hydrolysis.

We previously demonstrated inhibition of Na+-dependent 32Pi transport in canine renal brush-border membranes in association with NAD+-induced ADP ribosylation of membrane protein(s) and postulated that NAD+ inhibits Pi transport across the brush-border membrane via ADP ribosylation. Recently it was shown that incubation of rat brush-border membrane with NAD+ resulted in release of Pi which was prevented by EDTA. It was proposed that NAD+-mediated inhibition of 32Pi transport might occur through this mechanism. To determine whether NAD+ inhibited 32Pi transport by a mechanism other than or in addition to release of Pi, we compared Na+-dependent 32Pi counterflow in brush-border membrane equilibrated with Pi or with Pi generated from NAD+. Release of Pi from NAD+ incubated with brush-border membrane was confirmed. The increased uptake of 32Pi which was demonstrated in brush-border membrane equilibrated with Pi was not measured when intravesicular Pi was generated from a concentration of NAD+ which effected ADP-ribosylation of brush border membranes (100 microM NAD+). In contrast, increased uptake of 32Pi was demonstrated when intravesicular Pi was generated from 1 microM NAD+ which did not effect ADP ribosylation. Mg2+-dependent ADP ribosylation of brush-border membrane incubated with NAD+ was demonstrated which persisted during the time interval of 32Pi uptake measurements. Our findings are compatible with the hypothesis that NAD+-induced ADP ribosylation of brush-border membrane protein(s) results in inhibition of Pi transport across the membrane in vivo. EDTA may act to prevent this inhibition in brush-border membrane by chelation of Mg2+ and decreased ADP ribosylation.

Pituitary regulation of the male-specific steroid 6 beta-hydroxylase P-450 2a (gene product IIIA2) in adult rat liver. Suppressive influence of growth hormone and thyroxine acting at a pretranslational leve;.

Oligonucleotide probes that distinguish between two closely related mRNAs encoding steroid 6 beta-hydroxylases of rat P-450 gene family CYP3A were used to individually assess their responsiveness to pituitary hormone regulation. Northern blot analysis revealed that the elevation of immunoreactive P-450 IIIA2 in livers of hypophysectomized rats reflects an elevation of the constitutive, male-specific P-450 IIIA2 (P-450 2a) and not an induction of the drug-inducible P-450 IIIA1 (P-450p). P-450 IIIA2 mRNA levels in intact adult male rats were found to be markedly reduced by GH administered as a continuous infusion at levels as low as 1 mU/h, indicating that GH acts at a pretranslational step to suppress expression of this P-450 enzyme. In hypophysectomized male rats, however, this same hormone treatment was only partially effective at suppressing P-450 IIIA2 mRNA and protein, suggesting that other pituitary-dependent factors contribute to the suppression observed in the intact rats. Further analysis revealed that T4, but not ACTH or human CG, can act in concert with GH to effect a more complete suppression of hepatic P-450 IIIA2 mRNA and protein in hypophysectomized rats. T4 also suppressed the expression of another GH-regulated, male-specific hepatic enzyme, designated P-450 IIA2 (P-450 RLM2), particularly in hypophysectomized female rats. In contrast, the GH-responsive P-450 IIA1 (P-450 3) was much less affected by T4 treatment. Thus, while T4 can modulate P-450 IIIA2 expression, it does not serve as a universal regulator for hepatic expression of GH-responsive P-450s.

The effects of calcium and magnesium on the secretion of parathormone and parathyroid secretory protein by isolated porcine parathyroid cells.

The preparation of dispersed parathyroid cells by collagenase digestion of porcine parathyroid glands, essentially as outlined by Brown et al. (Endocrinology 99: 1582, 1976), is described. The cells secrete parathormone linearly for at least 4 h of incubation and rapidly respond in inverse fashion to changes in the medium calcium and magnesium concentrations over the range 0.5-3.0 mM. In terms of inhibition of secretion, either ion was more effective in the presence of a minimum concentration of the other, indicating that calcium and magnesium affect separate cellular sites. Parathormone was identified both by immunoassay of the whole incubation medium and by its separation by polyacrylamide gels and carboxymethylcellulose chromatography. When the cells were incubated with radioactive amino acids and both the medium and cells were subsequently analyzed on gels, we found that parathyroid secretory protein as well as parathormone and some immunoactive fragments were present. Analysis of the radioactive protein contained in the cells at high and low calcium concentrations revealed that calcium decreased the formation of the secretory protein by approximately 40% without appreciably affecting the formation of proparathormone or parathormone. The secretion of both parathyroid secretory protein and parathormone were inversely proportional to the concentrations of medium calcium or magnesium. The secretion of the latter, however, was more sensitive (95% inhibition) than parathormone (40-60% inhibition) to changes in medium divalent cations. These results suggest that the synthesis, intracellular processing, or secretion of parathormone and parathyroid secretory protein utilize independent calcium- and magnesium-regulated pathways.

Female-predominant rat hepatic P-450 forms j (IIE1) and 3 (IIA1) are under hormonal regulatory controls distinct from those of the sex-specific P-450 forms.

Hepatic expression of cytochrome P-450j (alcohol-inducible nitrosamine demethylase; P-450 gene IIE1) and P-450 3 (testosterone 7 alpha-hydroxylase; P-450 gene IIA1) is female predominant in adult rats [female/male greater than or equal to 1.5-2 (P-450j) or 3-4 (P-450 3)]. This sex difference emerges during the postsuckling period, when P-450 3 declines significantly (60-70% decrease) in male, but not female, rats, and P-450j declines in both sexes, but to a lower constitutive level in males than in females. The biochemical factors and regulatory events that control these developmental changes were investigated and found to be distinct from those that regulate expression of the female-specific hepatic enzymes P-450 2d (P-450 gene IIC12) and steroid 5 alpha-reductase. Immunoquantitation of the changes in P-450j and P-450 3 levels in hormonally altered rats established that both P-450s are under gonadal control. However, while androgen and estrogen both suppress P-450j expression, estrogen stimulates and androgen suppresses the expression of P-450 3. Since many of the effects of gonadal hormones on hepatic enzyme levels are mediated by the pituitary, the contribution of pituitary hormones to P-450j and P-450 3 expression was evaluated. Hypophysectomy of adult rats of either sex elevated P-450j to the levels found in immature rats (3- to 5-fold increase). This elevation was largely reversed in both sexes by GH administered either intermittently or continuously, demonstrating that P-450j is under the suppressive control of this pituitary hormone. The regulation of P-450 3 was more complex. Hypophysectomy elevated P-450 3 to prepubertal levels in adult male rats, but had no effect on P-450 3 levels in adult females. In both sexes GH suppressed P-450 3 expression when administered to hypophysectomized rats intermittently, but stimulated P-450 3 expression when infused continuously. Corresponding changes in hepatic microsomal P-450 3-dependent testosterone 7 alpha-hydroxylase and P-450j-dependent aniline hydroxylase activities were observed in response to hypophysectomy and GH replacement, but only after supplementation of microsomal NADPH P-450 reductase [which was 63-77% suppressed by hypophysectomy] with exogenous purified NADPH P-450 reductase. These studies demonstrate that these female-predominant hepatic P-450 enzymes are regulated by different mechanisms, and that both are under hormonal regulatory controls distinct from those that govern expression of the female-specific hepatic enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Cosecretion of secretory protein-I and parathormone by dispersed bovine parathyroid cells.

A RIA with a minimal sensitivity of 0.5 ng protein was developed for the measurement of bovine secretory protein-I (SP-I). With this assay and a previously established RIA for parathormone, the secretion and cell content of SP-I and parathormone were determined in dispersed bovine parathyroid cells. SP-I and parathormone were secreted in linear fashion over a 2-h period. The net secretion of both of these proteins diminished progressively as the concentration of calcium was raised from 0.25 mM to 3.0 mM. The molar ratio for the secreted proteins and those remaining in the cell varied from experiment to experiment but on average was 0.70 +/- 0.07 for the secreted proteins and 0.47 +/- 0.03 for the cellular proteins. Possible explanations for the difference in the ratio of SP-I to parathormone between cellular and secreted proteins include 1) a preferential secretion of SP-I; 2) a preferential intracellular degradation of SP-I; 3) a preferential postsecretory degradation of parathormone, or 4) differential affinities of potential fragments of either or both proteins for their antisera. These results suggest that SP-I and parathormone bear close but not identical metabolic and secretory fates.

Depletion of serum growth hormone in adult female rats by neonatal monosodium glutamate treatment without loss of female-specific hepatic enzymes P450 2d (IIC12) and steroid 5 alpha-reductase.

The sexually dimorphic profiles of pituitary GH secretion play a key role in regulating the expression of several sex-dependent and developmentally controlled P-450 enzymes in rat liver. Current models for P-450 regulation by GH, however, are primarily based on hypophysectomy and GH replacement experiments. The present study examines the effects on hepatic P-450 expression of neonatal injections of monosodium glutamate (MSG), which allows for the nonsurgical suppression of adult GH levels. Furthermore, the levels of other pituitary-dependent hormones, such as testosterone and estradiol, are largely unchanged in the MSG-treated rats. Although hypophysectomy and GH replacement experiments have previously demonstrated that expression of the female-specific hepatic enzymes P-450 2d (gene product IIC12) and steroid 5 alpha-reductase is strikingly dependent on continuous GH exposure, neither enzyme was decreased in adult female rat liver after the elimination of plasma GH (less than 2 ng/ml) by neonatal MSG treatment. Moreover, although the loss of circulating GH appears to be largely responsible for the more than 10- to 20-fold elevation of the male-specific hepatic P-450 forms 2a (gene product IIIA2) and RLM2 (gene product IIA2) in hypophysectomized female rats, no such elevation of the male-specific P-450s was observed in the GH-deficient MSG-treated female rats. In contrast, the female-predominant forms P-450j (gene product IIE1) and 3 (gene product IIA1) were both elevated in adult rat liver after neonatal MSG treatment, in agreement with earlier hypophysectomy studies and demonstrating the suppressive effects that GH can exert on expression of these P-450 forms. Thus, although MSG and hypophysectomy both produce GH depletion, the responsiveness of the hepatic P-450s to these endocrine manipulations differs, allowing for an expanded understanding of the role of GH in P-450 expression.

Signalling elements in the ultradian rhythm of circulating growth hormone regulating expression of sex-dependent forms of hepatic cytochrome P450.

Neonatal male rats were treated with monosodium glutamate (MSG) at either 2 or 4 mg/g BW on alternate days during the first 10 days of life. As adults, the 4 mg MSG-treated rats displayed the obesity, growth retardation, and reduced pituitary weights that typify this syndrome. These animals had no detectable plasma GH as determined from serial blood samples taken every 20 min for 8 consecutive h. Associated with this loss of circulating GH was an induction of the female-specific hepatic cytochrome P450 2d (gene IIC12) and the disappearance of the male-specific form of cytochrome P450 2c (gene IIC11). The catalytic activities of cytochrome P450 2c (i.e. androgen 16 alpha- and 2 alpha-hydroxylase), sex-dependent hexobarbital hydroxylase and total cytochrome P450 were similarly feminized. Rats exposed to the 2-mg dose of MSG were also obese, but their growth rates and pituitary sizes were not as severely affected as in the 4 mg MSG-treated rats. Circulating GH in these lower dosed males was secreted in a pulsatile pattern similar to that in normal males, except that the pulse amplitude was reduced as much as 90%. In spite of this profound decline in GH peak heights in the 2 mg MSG-treated males, liver metabolism was characteristically masculine. That is, female-specific cytochrome P450 2d remained undetectable, while the male forms of cytochrome P450 2c, 2a (gene IIIA2), and RLM2 (gene IIA2), their respective catalytic steroid hydroxylase activities, and associated sex-dependent drug-metabolizing enzymes were expressed at the level of or greater than that in normal males. Thus, while an ultradian pulse of circulating GH is necessary for the characteristically masculine profile of sex-specific forms of hepatic cytochrome P450, neither the amplitude of the secretory peaks nor their total GH content is critical, and these can be greatly reduced from the normal male levels.

IRIDIUM exposure increases c-fos expression in the mouse brain only at levels which likely result in tissue heating.

With the rapid development of wireless communication technology over the last 20 years, there has been some public concern over possible health effects of long-term, low-level radiofrequency exposure from cellular telephones. As an initial step in compiling a database for risk analysis by government agencies, the effects of 1-h exposure of mice to a 1.6-GHz radiofrequency signal, given as either a continuous wave or pulse modulated at 11 Hz with a duty cycle of 4:1 and a pulse duration of 9.2 ms IRIDIUM), on c-fos gene expression in the brain was investigated. The IRIDIUM signal is the operating frequency for a ground-to-satellite-to-ground cellular communications web which has recently become fully operational, and was named as such due to the original designed employment of the same number of low orbiting satellites as there are electrons orbiting the nucleus of an iridium atom. The expression of c-fos was not significantly elevated in the brains of mice until exposure levels exceeded six times the peak dose and 30 times the whole body average dose as maximal cellular telephone exposure limits in humans. Higher level exposure using either continuous wave (analog) or IRIDIUM signals elevated c-fos to a similar extent, suggesting no obvious pulsed modulation-specific effects. The pattern of c-fos elevation in limbic cortex and subcortex areas at higher exposure levels is most consistent with a stress response due to thermal perception coupled with restraint and/or neuron activity near thermoregulatory regions, and not consistent with any direct interaction of IRIDIUM energy with brain tissue.

The FEL (AF-4) protein donates transcriptional activation sequences to Hrx-Fel fusion proteins in leukemias containing T(4;11)(Q21;Q23) chromosomal translocations.

The t(4;11) chromosomal translocation marks a subset of acute lymphoblastic and secondary myeloid leukemias. It results in the fusion of the FEL (AF-4) gene on chromosome band 4q21 with the HRX (MLL) gene on chromosome band 11q23. This translocation results in the expression of fusion transcripts from both translocated chromosomes, with the derivative 11 product (fusing the amino-terminal third of the Hrx protein to the C-terminal two-thirds of the Fel protein) thought to be involved in leukemic transformation. The mechanism of transformation by Hrx-Fel in leukemic cells, however, is unknown and the specific leukemogenic contributions of Fel have not been defined. In this study, we demonstrate that Fel is capable of activating transcription from a minimal adenoviral E1b promoter as a Gal4-Fel fusion protein in transient transcriptional assays. The Fel transactivating sequences were localized to amino acids 365-572 which are consistently retained by Hrx-Fel fusion proteins created by t(4;11) translocations in leukemias. Furthermore, we demonstrate that the transactivation properties of Fel vary in different cell types. While Gal4-Fel constructs strongly activated transcription in Cos-7 cells and the MCF-7 breast tumor cell line, they displayed low to no activity in the precursor B-cell line REH, breast tumor cell line Gl-101A and epithelial-derived A431 cells. These data are consistent with a potential role of Hrx-Fel as a chimeric transcription factor in which Fel contributes transcriptional effector properties and suggest the requirement for cell-specific accessory factors.

The role of growth factors, cytokines, and vasoactive compounds in obstructive nephropathy.

Renal interstitial inflammation and fibrosis occurs after ureteral obstruction. Fibrosis most likely develops as a consequence of an imbalance between extracellular matrix synthesis and deposition and the degradation and removal of matrix. Angiotensin II is rapidly stimulated after the onset of ureteral obstruction. Angiotensin II in turn upregulates other factors (transforming growth factor beta, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants). Blockade of angiotensin II synthesis or inability of this peptide to bind to its receptor lessened the increased levels of mRNA for TGF-beta and collagen IV. Increased levels of angiotensin II have a major role in the development of tubulointerstitial fibrosis after ureteral obstruction.

Injury in the era of genomics.

The traditional approach to the study of biology employs small-scale experimentation that results in the description of a molecular sequence of known function or relevance. In the era of the genome the reverse is true, as large-scale cloning and gene sequencing come first, followed by the use of computational methods to systematically determine gene function and regulation. The overarching goal of this new approach is to translate the knowledge learned from a systematic, global analysis of genomic data into a complete understanding of biology. For investigators who study shock, the specific goal is to increase understanding of the adaptive response to injury at the level of the entire genome. This review describes our initial experience using DNA microarrays to profile stress-induced changes in gene expression. We conclude that efforts to apply genomics to the study of injury are best coordinated by multi-disciplinary groups, because of the extensive expertise required.

The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease.

A number of kidney diseases, and their progression to end-stage renal disease, are driven, in part, by the effects of angiotensin II. Increasing levels of angiotensin II may in turn up-regulate the expression of growth factors and cytokines, such as transforming growth factor-beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), osteopontin, vascular cell adhesion molecule-1 (VCAM-1), nuclear factor-kappaB (NF-kappaB), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor. Most of these compounds promote cell growth and fibrosis. Angiotensin II also stimulates oxidative stress. This stress in turn may potentiate the vasoconstrictor effect of the peptide due, in part, to increased catabolism of nitric oxide (NO). Oxidative stress, fueled in part by angiotensin II, up-regulates the expression of adhesion molecules, chemoattractant compounds and cytokines. The angiotensinogen gene, which provides the precursor for angiotensin production, is stimulated by NF-kappaB activation. NF-kappaB is activated by angiotensin in the liver and in the kidney. This provides an autocrine reinforcing loop that up-regulates angiotensin production. Angiotensin II activates NF-kappaB through both AT1 and AT2 receptors. In addition, angiotensin-converting enzyme (ACE) inhibition markedly decreases NF-kappaB activation in the setting of renal disease.

Comparative study of ACE inhibitors and angiotensin II receptor antagonists in interstitial scarring.

Many of the pathophysiologic events associated with kidney disease are driven by angiotensin II. Irrespective of the etiology, many kidney diseases lead to tubulointerstitial inflammation, fibrosis and loss of renal function. Contributors to the process of tubulointerstitial fibrosis include monocyte/macrophage infiltration, the synthesis of profibrotic cytokines such as transforming growth factor beta 1 (TGF-beta 1), interstitial myofibroblast proliferation, and clusterin expression. These processes are ameliorated by angiotensin converting enzyme (ACE) inhibition. Blockade of the angiotensin II receptor (AT-1) impaired fibroblast proliferation, consequent differentiation into myofibroblasts, and the synthesis of TGF-beta 1, but did not prevent monocyte infiltration. TGF-beta 1 synthesis or fibroblast proliferation but prevented the differentiation of fibroblasts into myofibroblasts and blocked clusterin expression. The nuclear factor-kappa B (NF-kappa B) family of transcription factors regulates genes involved in inflammation, proliferation and differentiation. ACE inhibition, AT-1 and AT-2 receptor blockade each differentially attenuated NF-kappa B isotype activation. The changes in NF-kappa B isotype may account for the variation seen in the pharmacologic effect of angiotensin II formation or action on the fibrotic process. When considering therapeutic options to prevent renal disease progression, one must be aware of the impact of transcription factors on the injured kidney and the consequent changes in cell infiltration, proliferation and differentiation.

Control of p53 and p21 (WAF1) expression during unilateral ureteral obstruction.

Long-term unilateral ureteral obstruction (UUO) initiates a series of renal events leading to proliferation of interstitial fibroblasts and proliferation/repair of tubular cells. This is evidenced by significant increases in proliferating cell nuclear antigen (PCNA) positive nuclei during UUO. Several pathologic settings requiring DNA replication and/or DNA repair are dependent upon the expression of p53 and at least one of two p53-dependent proteins, termed p21 (also called WAF1) and GADD45. We therefore sought to determine if p53, p21 (WAF1) or GADD45 mRNA levels were changed in obstruction. There was a progressive increase in the amount of p53 mRNA and p21 (WAF1) mRNA at 1, 3, 5 and 8 days of continuous UUO. The amount of GADD45 mRNA was found not to change. Treatment of the experimental animals with an ACE inhibitor on day 4 through day 8 of UUO significantly blunted the increase in p53 and p21 (WAF1) expression. ACE inhibitor treatment also significantly decreased the number of PCNA-positive renal cell nuclei during UUO. These results suggest that during ureteral obstruction the p53 and p21 (WAF1) genes are activated. ACE inhibitor treatment reduces p53 and p21 (WAF1) expression. This reduction is at least in part due to an inhibition of interstitial cell proliferation.

The effect of ACE inhibitors on the expression of matrix genes and the role of p53 and p21 (WAF1) in experimental renal fibrosis.

Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (AII). In this study we administered the angiotensin converting enzyme (ACE) inhibitor enalapril to rats with UUO after tubulointerstitial fibrosis was established. Treatment with the ACE inhibitor halted the progression of fibrosis and to a significant extent reversed some aspects of tubulointerstitial fibrosis. It is suggested that enalapril administration may be an effective means of preventing the progression of tubulointerstitial fibrosis.