Circulation time in man from lung to periphery as an indirect index of cardiac output.

Circulation time (Ct) between lung and periphery may be a surrogate for cardiac output, estimated here, for the most part, as the time between taking a breath of nitrogen and peripheral detection of a desaturation pulse. Use of pulse oximetry involves an internal, instrument delay; however, using the ear, we found shortening with exercise (12.1 +/- 0.37 sec, at rest; 9.1 +/- 0.25 sec at 100 watts), lengthening after beta-blockade, and lengthening in patients with echocardiographic and clinical left heart failure (8 patients 16.2 +/- 1.1 sec; 6 controls 12.0 +/- 0.5 sec). Pulse oximetry failed, however, to discriminate heart failure from normal in several patients. In patients referred to a department of nuclear medicine for assessment of chest pain, pulse oximetry (finger and ear) showed unacceptable variability. Nuclide delays between lung and carotid artery correlated significantly with the reciprocal of gated SPECT estimated cardiac output (Q(gs)); not so, however, for lung to finger. In normal subjects, an old Waters fast response oximeter gave short, reproducible Ct estimates and a significant correlation with the reciprocal of (indirect Fick) cardiac output (Q(if)). The relationship for normal subjects was: Ct = 0.28 x 60/Q(if) + 2.8 sec (Q(if) in L min.; P slope < .001).

Urine electrolytes as markers of bulimia nervosa.

OBJECTIVE: The diagnosis of bulimia nervosa (BN) is often delayed because patients are frequently secretive about the illness. Prior work has examined several potential diagnostic markers, none of which has been both highly sensitive and specific. Little is known about the utility of urine electrolytes in detecting BN symptoms. METHOD: Seventy-seven women with BN and 53 control women participated in the study. Urine and serum electrolytes and urine phenolthalein screens were obtained. Subjects with BN also completed a self-report instrument (the Eating Behaviors IV) regarding vomiting during the week prior to assessment. Receiver operating characteristic analysis was used to examine the predictive abilities of urine and serum electrolytes. RESULTS: Bulimic and control subjects differed significantly on most electrolyte measures. The ratio of urine sodium to urine chloride was the best predictor of bulimic behavior; selecting individuals with a ratio of >1.16 identified 51.5% of BN subjects with a 5% false-positive rate. Fractional excretion of sodium (FENA), urine anion gap (UAG), and serum potassium values were also predictive of BN but serum hypokalemia was not more common in BN than in control subjects (4.1% vs. 0%; p =.15). Vomiting frequency was correlated with an abnormal UAG (r(2) =.2231) but not FENA, nor serum potassium. CONCLUSION: The ratio of urine sodium to urine chloride is a useful predictor of bulimic behavior that appears to be more powerful in detecting BN than traditional screening measures such as serum hypokalemia.

Aldosterone in progressive renal disease.

Blockade of the renin-angiotensin-aldosterone system has proven effective in retarding progression of renal disease in the remnant kidney model, as well as other experimental diseases, and, most importantly, in a range of progressive human renal diseases. Attention has focused on the role of angiotensin II (Ang II) in propagating progression both by its hemodynamic and nonhemodynamic actions. Recent evidence, predominately in the remnant kidney model, indicates that the drugs used to block this hormone system, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, also lower aldosterone levels. Thus, aldosterone, as well as angiotensin II, appears to be instrumental in sustaining the hypertension and fibroproliferative destruction of the residual kidney.

Clusterin regulates vascular smooth muscle cell nodule formation and migration.

Vascular smooth muscle cells (VSMC) are the principal cellular component of the blood vessel wall where they exist in a differentiated state to maintain vascular tone. However, VSMC are not terminally differentiated and can be induced to dediffentiate, proliferate, and migrate. In fact, smooth muscle cell migration from the vascular wall into the lumen of the vessel is a central feature of occlusive vascular pathologies including atherosclerosis and intimal hyperplasia. In vitro, in the presence of an extracellular matrix, cultured vascular smooth muscle cells can migrate and invade the underlying gelatinous matrix, form multicellular nodular aggregations, and secrete the glycoprotein clusterin. Nodular cultures appear to mimic some of the properties of differentiated VSMC, in vivo. Here, to test the hypothesis that clusterin functions to modulate the formation of VSMC nodules and to facilitate cell migration a clusterin negative VSMC clone, SM-CLU13AS (Moulson and Millis, 1999, J Cell Physiol 180:355), was transiently transfected with plasmid pRcCMVCLU that contains the full-length porcine clusterin cDNA sequence under control of the CMV promoter. The transiently transfected VSMC culture expressed and secreted clusterin and formed nodules. To determine if clusterin regulates VSMC migration we used modified Boyden chamber assays. Clusterin, at 10 microg/ml, clearly promotes VSMC migration. In addition, a 15 amino acid synthetic peptide, representing amino acids 118-132 [KQTCMKFYARVCRSG] of the mature clusterin polypeptide, inhibits VSMC attachment to gelatinous substrate. Finally, clusterin appears to have a role in regulating endogenous clusterin expression in the clusterin negative clone. These results clearly establish that clusterin has functional role in VSMC nodule formation and support the conclusion that clusterin is a critical component of smooth muscle cell phenotypic modulation.

Aldosterone in renal disease.

Blockade of the renin-angiotensin-aldosterone system has proved effective in retarding the progression of renal disease in the remnant kidney model, as well as other experimental diseases, and most importantly, in a range of progressive human renal diseases. Attention has focused on the role of angiotensin II in propagating progression both by its hemodynamic and non-hemodynamic actions. Recent evidence, predominantly in the remnant kidney model, indicates that the drugs used to block this hormone system, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, also lower aldosterone levels. Aldosterone as well as angiotensin II thus appears to be instrumental in sustaining the hypertension and fibroproliferative destruction of the residual kidney.

Corneal morphology and sensitivity in lattice dystrophy type II (familial amyloidosis, Finnish type).

PURPOSE: To describe the corneal abnormalities and to measure different modalities of corneal sensitivity in corneal lattice dystrophy type II (familial amyloidosis, Finnish type, also known as gelsolin-related amyloidosis and originally as Meretoja syndrome). METHODS: Twenty eyes of 20 patients were examined by in vivo confocal microscopy and noncontact gas esthesiometry. RESULTS: Pleomorphism of, and dense deposits between or posterior to, the basal epithelial cells were frequently observed, as well as a reduction of long nerve fiber bundles in the subbasal nerve plexus. The anterior stroma was altered in most cases, with fibrosis and abnormal extracellular matrix. In 15 corneas, thick anterior and midstromal filaments, corresponding to lattice lines, and in 11 corneas, thin undulated structures were observed. The average mechanical sensitivity threshold of 12 subjects was increased, and in the remaining 8 subjects there was no response, even to the highest intensity of stimuli used. Three patients did not respond to CO(2), 11 to heat, and 2 to cold, but those patients who responded had normal thresholds. Patients with more long nerve fiber bundles per confocal microscopic image had better mechanical and cold sensitivity than patients with fewer nerve fiber bundles. CONCLUSIONS: Lattice lines seem to be related to amyloid material and not to corneal nerves. However, the subbasal nerve density appears reduced, which results mainly in a decrease in mechanical and, to a lesser extent, thermal sensitivity. The location of stromal filaments and undulated structures changes with increasing age.

Development and implementation of a web-based evaluation system for an internal medicine residency program.

Evaluation and feedback are fundamental components of graduate medical education. Paper-based evaluation systems are inefficient and costly and the evaluation data they provide are difficult to retrieve and analyze. In view of these problems, in 1996-1997, the authors developed and implemented a World Wide Web-based electronic evaluation system for the internal medicine residency program at the University of Minnesota. Residents were evaluated using the American Board of Internal Medicine Resident Evaluation Form. Custom evaluations were created for the assessment of sites, rotations, and faculty. The evaluations were completed by accessing an evaluation Web site from any location using standard computers and Web browsers. The evaluations were submitted electronically and automatically entered into a database. The system tracked compliance and automatically sent out reminders. Other features of the system included extensive reporting capabilities, automatic notification of substandard performance, and the ability to send confidential information to the program director. The total compliance rate ranged between 81% and 92% during the first 12 months of operation, with no significant difference in compliance observed between faculty and residents. The system was easy to use and could quickly and confidentially identify performance problems of residents and faculty from large numbers of evaluations.

Corneal structure and sensitivity in type 1 diabetes mellitus.

PURPOSE: Corneal wound healing is impaired in diabetic cornea. The purpose of this study was to examine patients with type 1 diabetes mellitus for changes in corneal morphology and to correlate corneal sensitivity, subbasal nerve morphology, and degree of polyneuropathy with each other. METHODS: Forty-four eyes of 23 patients with diabetes and nine control eyes were included. Corneal sensitivity was tested with a Cochet-Bonnet esthesiometer (Luneau, Paris, France), and corneal morphology and epithelial and corneal thickness were determined by in vivo confocal microscopy. The density of subbasal nerves was evaluated by calculating the number of long subbasal nerve fiber bundles per confocal microscopic field. The degree of polyneuropathy was evaluated using the clinical part of the Michigan Neuropathy Screening Instrument (MNSI) classification, and retinopathy was evaluated using fundus photographs. RESULTS: A reduction of long nerve fiber bundles per image was noted to have occurred already in patients with mild to moderate neuropathy, but corneal mechanical sensitivity was reduced only in patients with severe neuropathy. Compared with control subjects the corneal thickness was increased in patients with diabetes without neuropathy. The epithelium of patients with diabetes with severe neuropathy was significantly thinner than that of patients with diabetes without neuropathy. CONCLUSIONS: Confocal microscopy appears to allow early detection of beginning neuropathy, because decreases in nerve fiber bundle counts precede impairment of corneal sensitivity. Apparently, the cornea becomes thicker in a relatively early stage of diabetes but does not further change with the degree of neuropathy. A reduction in neurotrophic stimuli in severe neuropathy may induce a thin epithelium that may lead to recurrent erosions.

Predicting clinical outcome in the elderly renal transplant recipient.

BACKGROUND: The purpose of this study was to evaluate graft and patient survival in first-time kidney transplant recipients 60 years old or older, and to identify pretransplant risk factors that predict clinical outcome. METHODS: We reviewed the clinical course of 206 recipients, 60 years old or older, of first kidney transplants at the University of Minnesota. Patient and graft survival were compared with 1640 patients aged 18 to 59 transplanted during the same time period. Regression analysis was performed to identify risk factors that predicted a poor outcome. RESULTS: In patients 60 years old or older, graft survival at one and five years was 86 and 60%, and patient survival at one and five years was 90 and 68%, respectively. Graft and patient survival were decreased compared with recipients aged 18 to 59, but were similar when censored for patient death as a cause of graft loss. A pretransplant history of nonskin malignancy and vascular disease and a current smoking history were risk factors for decreased graft and patient survival. To determine the potential impact of screening for low-risk patients, we evaluated graft and patient survival in patients age > or =60 without these risk factors versus those with one or more risk factors. In the absence of risk factors, both graft and patient survival were significantly improved compared with patients with these risk factors and were equivalent to that of patients aged 18 to 59. CONCLUSIONS: Renal transplantation is a safe and effective therapy for the older renal failure patient. In the absence of identified risk factors, graft survival is equivalent to that seen in younger patients.

In vivo confocal microscopy of patients with corneal recurrent erosion syndrome or epithelial basement membrane dystrophy.

OBJECTIVE: To characterize morphologic changes in corneas of patients with recurrent erosion syndrome or epithelial basement membrane dystrophy using in vivo confocal microscopy. DESIGN: Observational case series PARTICIPANTS: Fourteen eyes of eight patients with diagnosed epithelial basement membrane dystrophy and 13 eyes of seven patients with recurrent erosion syndrome were examined. METHODS: Slit-lamp examination and in vivo confocal microscopy. The pathologic findings are presented as digitized images obtained from video tape recorded during the confocal microscopy. MAIN OUTCOME MEASURES: The morphology of corneal surface epithelial cells, basal epithelial cells, subbasal nerve plexus, Bowman's layer, stromal keratocytes, and endothelium was analyzed. RESULTS: The surface epithelium was intact in all but two eyes. One cornea (a basement membrane disorder with clinically visible dots) had multinucleate surface epithelial cells, and one eye with recurrent corneal erosions showed a freely floating surface epithelium sheet in the tear fluid. Patients in both groups showed islets of highly reflective cells with presumed intracellular deposits surrounded by normal cells in the basal epithelial cell layer. The basal epithelial cell area also showed other pathologic changes, including drop-shaped configurations, streaks, or ridges. Folding of the Bowman's layer was also observed in both groups. Anterior keratocytes showed signs of activation (highly reflective nuclei with visible processes) in some of the patients regardless of the clinical diagnosis, and in recurrent erosions even increased deposition of abnormal extracellular matrix in the anterior stroma was suspected. Posterior corneal keratocytes and endothelium appeared normal when examined. The subbasal nerve plexus showed various pathologic changes, such as short or strangely shaped nerve fiber bundles, decreased numbers of long nerve fiber bundles, only faintly visible long nerve fiber bundles (instead of the normally observed long parallel running interconnected bundles), or increased amounts of Langerhans cells, but only one patient (with recurrent erosion syndrome) lacked the subbasal nerve plexus. CONCLUSIONS: In vivo confocal microscopy of corneas with recurrent erosions or epithelial basement membrane dystrophy showed deposits in basal epithelial cells, subbasal microfolds and streaks, damaged subbasal nerves, or altered morphology of the anterior stroma. Confocal microscopy cannot replace biomicroscopy in making a specific diagnosis, but it sometimes helps the diagnosis in corneas that appear normal under a biomicroscope.

Iliac artery stenosis masquerading as diuretic resistant congestive heart failure.

Iliac artery stenosis is a rare cause of renal dysfunction in renal allograft recipients. Its presence can mimic renovascular hypertension and yet alter the very radiologic tests used to diagnose renal artery stenosis. We investigate a case of iliac artery stenosis that presented with diuretic resistant fluid overload, hypertension and limb claudication that exposed the pitfalls in the diagnosis and management of this condition. Successful stent placement, 8 months after transplant, resulted in return of the serum creatinine below the post-transplant nadir.

Identification of clusterin sequences mediating renal tubular cell interactions.

Expression of the glycoprotein clusterin is markedly increased following tissue injury. One function of clusterin is to promote cell interactions which are perturbed in these pathologic settings. Clusterin causes cell aggregation and adhesion in vitro yet the molecular mechanism for this effect is not known. In order to identify the active site(s) of clusterin, 34 peptides, each 15 amino acid residues in length, were synthesized from hydrophilic regions of human clusterin. When studied individually, none of the peptides caused aggregation of LLC-PK1 cells, a porcine renal epithelial cell line. However, two out of the 34 peptides inhibited clusterin-induced cell aggregation in a dose-dependent manner. Scrambled versions of these two 'active' peptides did not inhibit cell aggregation. Seven peptides promoted cell adhesion. In conclusion, these findings provide evidence for novel amino acid sequences mediating clusterin-induced renal cell interactions.

Tumour necrosis factor alpha (TNFalpha) in tears of atopic patients after conjunctival allergen challenge.

BACKGROUND: Proinflammatory cytokines, such as TNFalpha are involved in the pathogenesis of allergic rhinitis and asthma. OBJECTIVE: Our aim was to study the tear fluid TNFalpha levels in atopic patients before and after topical ocular allergen challenge. METHODS: Thirteen patients were first challenged with topical allergen in the left eye and then dilution buffer in the right eye. Tear fluid samples were collected before the challenges and after 5, 30 and 60 min. Clinical symptoms were scored. Tear fluid TNFalpha concentrations were measured using a double-antibody radioimmunoassay. TNFalpha release rates were calculated using the tear fluid flow in the collection capillary as an estimate for the tear secretion rate. RESULTS: The mean baseline TNFalpha concentrations (ng/L) were 1310 (allergen-challenged eye) and 967 (control eye), and release rates (pg/min) 1.81 (allergen-challenged eye) and 1.39 (control eye), respectively. In the allergen-challenged eye, TNFalpha concentrations and release rates were 1479 and 4.30 (5 min), 1367 and 3.20 (30 min) and 1426 and 3.80 (60 min). In the control eye, TNFalpha concentrations and release rates were 746 and 0.67 (5 min), 1001 and 0.92 (30 min) and 1504 and 1.05 (60 min). The release rates of the allergen-challenged eye were significantly increased at all time points after the challenge when compared with the baseline or the control eye. CONCLUSION: Increased TNFalpha release rates suggest that this cytokine is an early mediator of allergy after conjunctival challenge.

Clusterin protects against oxidative stress in vitro through aggregative and nonaggregative properties.

Perturbations of cell interactions, an early event in acute renal injury, have important pathophysiologic consequences. We hypothesized that promotion of cell interactions protects cells from injury. To test this hypothesis, a single cell suspension of LLC-PK1 cells (porcine proximal tubular cell line) treated with albumin (control) was compared to cells aggregated with fibrinogen or purified human clusterin (aggregation graded 0 to 4). Following aggregation, the cells were injured with 1.5 mM hydrogen peroxide (H2O2) for three hours. Cell aggregation induced by clusterin but not fibrinogen protected against oxidant injury by H2O2. Complete abrogation of cytotoxicity occurred at a clusterin concentration of 2.5 micrograms/ml, which resulted in an aggregation score of 1. In the absence of aggregation, clusterin at concentrations of 20 and 50 micrograms/ml, but not lower doses, partially protected against injury induced by H2O2. Cell aggregation induced by both clusterin and fibrinogen partially protected against endogenously generated oxidant stress induced by incubating LLC-PK1 cells with aminotriazole and 1-chloro-2,4-dinitrobenzene (CDNB). In conclusion, clusterin protects against models of oxidant stress in vitro, whether generated by exogenously administered hydrogen peroxide, or from endogenously produced peroxide, and such protective effects can accrue from aggregative and nonaggregative properties of clusterin.

Purinergic receptors mediate cell proliferation and enhanced recovery from renal ischemia by adenosine triphosphate.

Kidney dysfunction after ischemia can be improved by either limiting the initial injury or by enhancing the subsequent proliferative repair process. Adenosine triphosphate (ATP) favorably affects kidney function when it is given shortly after ischemia. We tested whether ATP promotes the proliferative repair response. Rats were subjected to occlusion of the left renal artery for 40 minutes and received an infusion of ATP, 12.5 micromol intravenously over 30 minutes, beginning at reperfusion. Control animals received saline solution or the hydroxyl radical scavenger dimethylthiourea (DMTU). Despite comparable functional protection by DMTU and ATP, only ATP specifically increased DNA synthesis (renal incorporation of tritiated thymidine) to an extent greater than that produced by ischemia alone. In other animals, ribonucleic acid was extracted from kidneys for Northern analysis. Expression of the proto-oncogenes c-fos and c-jun was enhanced in ATP-treated animals as compared with controls. Expression of a histone protein gene (H2b) and thymidine kinase was increased by ischemia but was not additionally affected by ATP. In vitro studies of primary cultures of renal proximal tubule epithelial cells confirmed the ability of ATP to stimulate cellular proliferation as a consequence of stimulation of purinergic P2 receptors, possibly of the P2x subclass. In summary, ATP given after ischemia increased new DNA synthesis and augmented expression of genes critical to cellular proliferation. These beneficial effects were not merely a consequence of limiting initial cellular damage, and they suggest a novel mechanism of action for ATP and other purinergic receptor agonists in renal ischemia.

Temporal induction of clusterin in the peri-infarct zone after experimental myocardial infarction in the rat.

Clusterin, a glycoprotein with potent cellular cohesive properties, is induced in many organs at times of tissue injury or remodeling. After renal infarction, for example, clusterin is localized to tubular epithelial cells in the peri-infarct zone. The purpose of this study was to examine the spatial and temporal expression of cardiac clusterin after myocardial infarction. Sprague-Dawley rats underwent permanent coronary ligation or sham operation. Hearts were harvested at 6 hours and at 2, 14, and 28 days after infarction. Cardiac clusterin expression was examined by immunohistochemistry and in situ hybridization. Left ventricular clusterin staining was evident at 6 hours and 2 days after myocardial infarction, although not at later time periods. Clusterin was localized to peri-infarct zone myocytes and endothelial cells of this region, and local synthesis of clusterin by myocytes was confirmed by in situ hybridization. Clusterin was not present in inflammatory cells or in left ventricular tissue distant from the infarct. The distribution of clusterin was different from the membrane attack complex of complement (C5b-9), with the latter being present diffusely throughout the infarct zone. Although the role of cardiac clusterin is not known, we speculate that clusterin's cohesive properties serve to promote myocyte interactions that are perturbed in the peri-infarct zone after myocardial infarction.

Redox regulation of renal DNA synthesis, transforming growth factor-beta1 and collagen gene expression.

Growth and injury represent recurrent and related themes in the study of progressive renal disease. We have previously demonstrated that a prooxidant diet, one deficient in antioxidants, selenium and vitamin E, induces renal enlargement, proteinuria, mild tubulointerstitial disease and diminished glomerular filtration rate (GFR). Our present study represents continued examination of these processes. We demonstrate that these diets increase thymidine incorporation into DNA and net DNA content in renal tissue, and induce expression of the mRNA for the proto-oncogene, c-myc, and the histone, H2b. We localize increased DNA synthesis as occurring mainly in the distal renal tubular epithelium. These deficient kidneys also exhibit interstitial expansion that parallels the pattern of DNA synthesis in that both processes are more prominent in the medulla than in the cortex. mRNAs for collagens I, III and IV in conjunction with transforming growth factor-beta1 (TGF-beta1) are up-regulated in the kidney in rats maintained on the deficient diet. In complementary in vitro studies, the exposure of rat kidney fibroblasts, NRK 49F cells, to noncytolytic doses of hydrogen peroxide, induces collagen III, collagen IV and TGF-beta1 mRNA. Induction of these genes is also observed in mesangial cells so exposed to noncytolytic doses of hydrogen peroxide. A final aspect of our study was the examination of renal generation of hydrogen peroxide and the profile of the hydrogen peroxide-degrading enzymes. Deficient kidneys exhibit increased mitochondrial generation of hydrogen peroxide independent of oxygen consumption but in conjunction with suppression of glutathione peroxidase mRNA and activity. Lipid peroxidation was increased twofold in the cortex and medulla of the deficient kidneys. Surprisingly, catalase activity, measured in the cortex and medulla, and whole kidney catalase mRNA were also reduced in rats maintained on the antioxidant deficient diet, effects that may further compromise the clearance of hydrogen peroxide. These changes in catalase represent an adverse response to this dietary deficiency, and may be relevant to decreased catalase activity described in chronic renal insufficiency. Thus, a chronic prooxidant state, with features that mimic those of clinical uremia, increases DNA synthesis of renal tubular epithelium, induces mRNA expression for collagens I, III and IV in conjunction with the mRNA for the fibrogenic cytokine, TGF-beta1. Oxidants also induce collagen III, collagen IV and TGF-beta1 mRNA in vitro.

Induction of clusterin in tubules of nephrotic rats.

Clusterin is a glycoprotein induced after renal tubular cell injury. The purpose of this study was to examine the expression of clusterin in a disease model characterized early in its course by predominant glomerular injury. Male Wistar rats (weighing 251 +/- 16 g) were treated with puromycin aminonucleoside (PAN: 15 mg/100 g body wt, subcutaneously; n = 7) or vehicle (control; n = 8). The kidneys were harvested 6 d after treatment, when rats were nephrotic. Clusterin mRNA was markedly induced in the kidneys of nephrotic rats (8.5-fold versus control). Immunohistochemistry studies demonstrated clusterin primarily in tubules in the cortex and medulla. Many of the tubules staining for clusterin were dilated but had no other differentiating morphologic features. Increased numbers of proliferating tubular cells were seen at 6 d, but there was no correlation between these cells and clusterin staining. In contrast to the extent and pattern of clusterin staining, vimentin was seen in only sporadic, dilated tubules, in addition to its expected glomerular localization. An increase in clusterin mRNA was not seen 1, 2, or 4 d after PAN injection. In conclusion, tubular epithelial cell induction of clusterin occurs in the kidneys of nephrotic rats. The appearance of clusterin precedes the development of tubulointerstitial disease and may be a response to the proteinuria.

Interaction of angiotensin II and TGF-beta 1 in the rat remnant kidney.

An interaction between angiotensin (Ang) II and transforming growth factor (TGF)-beta 1 is gaining increasing recognition. Ang II has been implicated in the progression of renal disease, and TGF-beta 1 is a potent fibrosis-promoting cytokine. We sought to determine whether the beneficial effects of renin-angiotensin system blockade on remnant kidney function were associated with a reduction in renal TGF-beta 1 in this model of chronic renal failure. After subtotal renal ablation, rats fed a 40% protein diet and treated with losartan not only had a reduction in systolic BP (96 +/- 8 versus 130 +/- 8 mmHg, P < 0.05, losartan versus control) and urinary protein excretion (4 +/- 5 versus 23 +/- 20 g/d, P < 0.05, losartan versus control), but also exhibited a reduction in renal TGF-beta 1 mRNA (194 +/- 64 versus 411 +/- 101 optical density units, P < 0.05, losartan versus control) and TGF-beta 1 protein levels (9.8 +/- 2.5 versus 18.6 +/- 5.8 ng/g of renal tissue, P < 0.05, losartan versus control). The elevation of TGF-beta 1 in the remnant kidney was most pronounced in the scar region (22.9 +/- 13.1 versus 5.8 +/- 3.7 ng/g, P < 0.05, scar versus nonscar). A combination of reserpine, hydralazine, and hydrochlorothiazide, although effective in lowering systemic BP in this model of chronic renal failure, was not associated with a reduction in proteinuria or TGF-beta 1. We conclude that in this model of progressive renal injury, Ang II antagonism may exert a beneficial effect in part by its negative influence on TGF-beta 1.