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Biomedical subjects

A B Fogo

Publications and source records attributed to A B Fogo.

At least 19 recordsLinked to original sources
PubMed2006

Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury.

This study tests the hypothesis that plasminogen activator inhibitor-1 (PAI-1) contributes to aldosterone-induced renal and cardiac injury. The effects of 12-week aldosterone (2.8 microg/day)/salt (1% drinking water) versus vehicle/salt on renal and cardiac histology and mRNA expression were determined in wild-type (WT) and PAI-1 deficient (PAI-1(-/-)) mice. Systolic blood pressure was similar in aldosterone-infused WT and PAI-1(-/-) mice until 12 weeks, when it was significantly higher in the WT mice. At 12 weeks, urine volume, sodium excretion, and sodium/potassium ratio were similarly increased in the two aldosterone-infused groups. In contrast, urine albumin excretion was greater in aldosterone-infused WT mice (mean+/-s.d.: 699.0+/-873.0 microg/24 h) compared to vehicle-infused WT (23.6+/-9.0 microg/24 h, P=0.003) or aldosterone-infused PAI-1(-/-) mice (131.6+/-110.6 microg/24 h, P=0.007). Aldosterone increased glomerular area to a greater extent in WT (4651+/-577 versus 3278+/-488 microm2/glomerulus in vehicle-infused WT, P<0.001) than in PAI-1(-/-) mice (3713+/-705 microm2/glomerulus, P=0.001 versus aldosterone-infused WT), with corresponding mesangial expansion. Renal collagen content was also increased in aldosterone-infused WT versus PAI-1(-/-) mice. In WT mice, aldosterone increased renal mRNA expression of PAI-1, collagen I, collagen III, osteopontin, fibronectin, monocyte chemoattractant protein-1 (MCP-1), and F4/80 (all P<0.05), but not transforming growth factor beta (TGF-beta). In PAI-1(-/-) mice, aldosterone increased renal expression of collagen I, osteopontin, fibronectin, and MCP-1, and tended to increase collagen III. Renal osteopontin expression was diminished in aldosterone-treated PAI-1(-/-) compared to aldosterone-treated WT mice (P=0.05). Aldosterone induced cardiac hypertrophy but not fibrosis in WT and PAI-1(-/-) mice. PAI-1 contributes to aldosterone-induced glomerular injury.

Albuminuria↗
PubMed2006

Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis.

We have previously observed increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in podocytes in both rat and human sclerotic conditions. The aim of the present study was to investigate whether activation of PPARgamma can attenuate podocyte injury-associated glomerulosclerosis in vivo. Puromycin aminonucleoside nephropathy was induced in Sprague-Dawley rats. The animals then either received no further treatment (control group (CONT)); or the PPARgamma agonist, pioglitazone (Pio) starting at week 0 (P0); or Pio starting at week 6 (P6), with sacrifice at week 12. At week 12, urinary protein excretion and systolic blood pressure were similar in the three groups. Glomerular filtration rate and glomerulosclerosis were decreased in CONT and P0 at week 12, but preserved in P6 rats. PPARgamma expression in CONT at 12 weeks was increased in podocytes and in mesangial WT-1 cells in segmentally sclerotic glomeruli, with less Wilms' tumor 1 (WT-1) staining. In P6 rats, mesangial WT-1 staining was lessened, but podocyte staining was strongly accentuated. Delayed treatment with Pio partially restored podocyte staining and tended to decrease the ratio of proliferating cell nuclear antigen-positive to apoptotic cells in glomeruli. Both treatment groups showed significantly reduced infiltrating glomerular macrophages and plasminogen activator inhibitor-1 mRNA expression in cortex, with no change in transforming growth factor-beta1 and tissue inhibitor of metalloproteinase-1 mRNA. Pio also decreased renal cortical angiopoietin-like protein 4 expression to almost 20% of CONT group, associated with increased vascular endothelial-derived growth factor expression in glomeruli. We conclude that treatment with PPARgamma agonist has protective effects on progression of glomerulosclerosis.

Angiopoietin-Like Protein 4↗
PubMed2006

The clot thickens.

Vascular sclerosis has been linked to many risk factors, including smoking, family history, low birth weight, and hypertension. In interesting studies, Goforth et al. show an increased rate of mutations in thrombophilic molecules in patients with vascular sclerosis in renal biopsies, suggesting yet another mechanism.

Biopsy↗
PubMed2001

Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition.

BACKGROUND: Long-term inhibition of nitric oxide synthase (NOS) is known to induce hypertension and perivascular fibrosis. Recent evidence also suggests that long-term NOS inhibition induces expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues and that PAI-1 may contribute to the development of fibrosis after chemical or ionizing injury. On the basis of these observations, we hypothesized that PAI-1 may influence the vascular response to long-term NOS inhibition by N(omega)-nitro-L-arginine methyl ester (L-NAME). METHODS AND RESULTS: We compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis in PAI-1-deficient (PAI-1(-/-)) and wild-type (WT) male mice (N=6 per group). At baseline, there were no significant differences in blood pressure between groups. After initiation of L-NAME, systolic blood pressure increased in both groups at 2 weeks. Over an 8-week study period, systolic blood pressure increased to 141+/-3 mm Hg in WT animals versus 112+/-4 mm Hg in PAI-1(-/-) mice (P<0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME-treated WT mice (P<0.01 versus PAI-1(-/-) mice). Cardiac type I collagen mRNA expression was greater in control (P<0.01) and L-NAME-treated PAI-1(-/-) (P<0.05) groups than in control WT mice, indicating that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. CONCLUSIONS: These findings suggest that PAI-1 deficiency alone is sufficient to protect against the structural vascular changes that accompany hypertension in the setting of long-term NOS inhibition. Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease.

Animals↗
PubMed2001

Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcriptional factors with beneficial effects in diabetes mediated by improved insulin sensitivity and lipid metabolism, but potential adverse effects in atherosclerosis by promoting in vitro foam cell formation. We explored whether a PPAR gamma agonist, troglitazone (TGL), affects sclerosis by mechanisms unrelated to insulin and lipid effects in a model of nondiabetic glomerulosclerosis. METHODS: Adult male Sprague Dawley rats underwent 5/6 nephrectomy and were treated for 12 weeks as follows: control (CONT), no further treatment; triple antihypertensive therapy (TRX); and TGL or TGL + TRX. Functional, morphological, and molecular analyses were performed. RESULTS: Systolic blood pressure (SBP) was increased in CONT and TGL groups (161 +/- 1 and 160 +/- 3 mm Hg), but not in TGL + TRX and TRX (120 +/- 3 vs. 126 +/- 1 mm Hg, P < 0.0001 vs. non-TRX). Serum triglyceride and cholesterol levels in all groups remained normal except for slightly higher serum cholesterol levels in TRX group. TGL groups had reduced proteinuria, serum creatinine, and glomerulosclerosis versus CONT, in contrast to no significant effect with TRX alone (sclerosis index, 0 to 4+ scale: CONT 1.99 +/- 0.42, TGL 0.85 +/- 0.12, TGL + TRX 0.56 +/- 0.14, TRX 1.30 +/- 0.21; TGL, P < 0.05; TGL + TRX, P = 0.01 vs. CONT). Glomerular cell proliferation, assessed by proliferating cell nuclear antigen (PCNA), was decreased after treatment with TGL or TGL + TRX, in parallel with decreases in glomerular p21 mRNA and p27 protein compared with CONT and TRX (PCNA + cells/glomerulus: CONT 2.04 +/- 0.64, TGL 0.84 +/- 0.21, TGL + TRX 0.30 +/- 0.07, TRX 1.38 +/- 0.37; TGL, P < 0.05, TGL + TRX, P < 0.01 vs. CONT). Glomerular plasminogen activator inhibitor-1 (PAI-1) immunostaining was decreased in TGL or TGL + TRX groups (0 to 4+ scale, CONT 2.42 +/- 0.32, TGL 1.40 +/- 0.24, TGL + TRX 1.24 +/- 0.17, TRX 2.53 +/- 0.24; TGL or TGL + TRX vs. CONT, P < 0.05), with a parallel decrease in PAI-1 mRNA by in situ hybridization. Glomerular and tubular transforming growth factor-beta (TGF-beta) mRNA expression was decreased with TGL treatment. Glomerular macrophages, present in CONT and TRX rats, did not express PPAR gamma, in contrast to PPAR gamma + macrophages in control carotid artery plaque. PPAR gamma was expressed in resident cells. CONCLUSIONS: Our results demonstrate in vivo that the PPAR gamma ligand TGL ameliorates the progression of glomerulosclerosis in a nondiabetic model. Macrophages show phenotypic diversity in glomerular versus vascular sclerosis, with macrophage PPAR gamma expression in only the latter. PPAR gamma beneficial effects are independent of insulin/glucose effects and are associated with regulation of glomerular cell proliferation, hypertrophy, and decreased PAI-1 and TGF-beta expression.

Animals↗
PubMed2001

Role of angiotensin II in glomerular injury.

The components of the renin-angiotensin system (RAS) in progressive renal disease have been extensively investigated, indicating multiple actions beyond hemodynamic and salt/water homeostasis. Studies in various human diseases and in animal models have shown that angiotensin (Ang) I-converting enzyme inhibitors (ACEI) are superior to other antihypertensive agents in protecting the kidney against progressive deterioration, even in conditions without systemic hypertension. These findings suggest that Ang II has nonhemodynamic effects in progressive renal disease. Interactions of the RAS with aldosterone and bradykinin may have impact on both blood pressure and tissue injury. The RAS is now recognized to be linked to induction of plasminogen activator inhibitor-1 (PAI-1) likely via both the type 1 (AT1) and type 4 (AT4) receptors, thus, promoting both thrombosis and fibrosis. A role of angiotensin in the regulation of immune injury and inflammation has also been identified. Polymorphisms of genes relevant to the RAS appear to affect the risk and course of cardiovascular and renal diseases and response to treatment. The beneficial effect on renal fibrosis of inhibiting the RAS likely reflects the central role that angiotensin has in regulating renal function and structure by its multifaceted actions. This article will focus on the role of the RAS in glomerular injury.

Aldosterone↗
PubMed2001

Renal fibrosis and the renin-angiotensin system.

These data demonstrate that regression of biopsy-proven glomerulosclerosis can be achieved in various experimental settings. The potential importance of the RAS in renal fibrosis is underscored by the effectiveness of therapies that aim to inhibit its manifold actions, including induction of PAI-1. An understanding of the interactions of the RAS with the immune response, aldosterone, and PAI-1, as well as the dynamic control of cell proliferation, apoptosis, and regeneration, is now evolving. Ongoing studies will establish which of these recent provocative findings from animal models are relevant to human diseases, and may lead to optimal therapies to fore-stall progression and perhaps even induce regression of sclerosis.

Animals↗
PubMed2000

The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis.

Regardless of the primary cause, progressive renal deterioration with sclerosis is a hallmark of many renal diseases. Several studies have shown the superiority of angiotensin-converting enzyme inhibitors compared with other antihypertensive agents in providing protection from progressive renal deterioration. Furthermore, animal studies have shown that angiotensin II antagonists in excess of antihypertensive doses can also ameliorate or reverse glomerulosclerosis, leading to the hypothesis that angiotensin II has nonhemodynamic effects that mediate the renoprotective effects shown in these investigations. Although historically angiotensin II has been associated with salt and fluid homeostasis, recent data show that angiotensin II induces cell growth and matrix accumulation in glomerular cells. Plasminogen activator inhibitor-1 has been shown to be the major inhibitor of tissue plasminogen activator and urokinase-like plasminogen activator, with potentially important effects not only on thrombosis/fibrinolysis, but also on matrix degradation because of the proteolytic actions of these substances. Angiotensin II has been shown to influence the actions of plasminogen activator inhibitor-1 and, consequently, its thrombotic and sclerotic effects. Various studies, both in vitro and in vivo, have shown that direct hemodynamic actions, modulation of endothelial injury, and growth factor actions also may be important in the development of sclerosis. These factors can be directly modulated by angiotensin II inhibition. Sclerosis may even be reversed when therapies augment matrix degradation processes, both by directly increasing proteolytic activity and by downregulating inhibitors of matrix degradation. These observations indicate that angiotensin II is important in fibrotic as well as thrombotic renal injuries that lead to progressive renal disease and also in the development of therapies such as specific angiotensin receptor antagonists to prevent or reverse these conditions.

Angiotensin II↗
PubMed2000

Immunomorphometric studies of proteinuria in individual deep and superficial nephrons of rats.

Heterogeneity of structure and function among nephrons is a well-recognized feature of chronic renal diseases. However, only a small number of superficial nephrons per kidney are accessible for micropuncture analysis and relationships of proteinuria to structural change in individual nephrons of experimental models are not clearly established. To directly evaluate proteinuria in many individual nephrons, we developed an immunomorphometric method of analysis. This method is based on the uniformly abundant renal synthesis of Tamm-Horsfall protein (THP) in the thick ascending limb of Henle's loop (TAL). Luminal rabbit immunoglobulin G (IgG) deposits are formed in TALs of proteinuric nephrons in rats injected with heterologous IgG anti-THP antibodies. This immunomorphometric luminal deposit method of assessing proteinuria was previously validated through analysis of heterologous immune complex nephropathy. Glomerular dysfunction in several models-spontaneously hypertensive rats (SHR), aging Sprague-Dawley (SD) rats, rats with adriamycin nephropathy (ADR), and rats subjected to subtotal nephrectomy (NX)-was characterized by immunomorphometric analysis after injection of anti-THP antibodies. Luminal IgG deposits were used to identify nephrons with increased proteinuria. Nephrons were identified histologically as either long looped (LL) or short looped (SL), and frequency of luminal deposits in these nephrons was determined. Glomerular size and sclerosis in deep and superficial zones of renal cortex were determined. Luminal deposits in LL nephrons were more frequent than luminal deposits in SL nephrons in SHRs (p < .001) and aging rats (p < .001) and SL nephrons in ADR rats (p < .02). Whole kidney levels of albuminuria correlated closely with the frequency of luminal deposits in both LL and SL nephrons of SHRs and ADR rats and in LL nephrons of aging rats (p < .005). In contrast, LL and SL deposits were equal in NX rats and did not correlate with albuminuria. A majority of luminal deposits extended beyond the first medullary TAL zone of NX rats, but was confined to this zone in the other 3 models. Deep cortical glomeruli were larger with more glomerulosclerosis than superficial cortical glomeruli. Albuminuria correlated with sclerosis of both deep (p < .002) and superficial (p < .01) glomeruli in NX rats, but not in the other three models. These studies provide a detailed characterization of a new method that allows comparison of proteinuria derived from deep and superficial nephrons. They also provide evidence that pathogenesis of the glomerulosclerosis in NX rats differs from that of the other three models. Glomerulosclerosis was closely linked to the overall level of albuminuria in NX rats, but not to luminal deposits. In the other three models, albuminuria and luminal deposits were closely linked but did not correlate with glomerulosclerosis. Furthermore, LL and SL nephron proteinuria of NX rats was comparable while LL proteinuria was markedly greater than SL proteinuria in the other three models. The luminal deposit method provides a new way to analyze heterogeneity of proteinuria among nephrons and the mechanisms underlying structural change in experimental glomerular diseases.

Animals↗
PubMed2000

Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo.

BACKGROUND: The fibrinolytic system plays an important role in degrading fibrin-rich thrombi and in vascular and tissue remodeling. Elevated levels of plasminogen activator inhibitor-1 (PAI-1) can reduce the efficiency of the endogenous fibrinolytic system. Angiotensin (Ang) has been shown to regulate PAI-1 expression via the Ang type 1 (AT1) receptor in some tissues and via the AT4 receptor in cultured endothelium. The purpose of this study was to examine the tissue-specific pattern of PAI-1 expression in response to infusion of Ang II in vivo. METHODS: Adult male Sprague-Dawley rats (N = 5 in each group) were treated with four hours of intravenous infusions of Ang II or vehicle control while mean arterial pressure (MAP) was monitored: group 1, 600 ng/kg/min Ang II; group 2, Ang II + 10 mg/kg of the AT1 receptor antagonist (AT1RA) L158-809 q2 hour; group 3, Ang II + 0.01 to 0.1 mg/kg hydralazine as required to maintain normal blood pressure; and group 4, saline-infused controls. After infusion, tissue was harvested for Northern blotting, immunohistochemical analysis, and in situ hybridization. RESULTS: In group 1, Ang II infusion increased MAP from 105 +/- 8 to 160 +/- 9 mm Hg (mean +/- SE, P < 0. 01). Ang II induced increased expression of PAI-1 mRNA in all tissues examined from 5.1-fold in the heart, 9.7-fold in the kidney, 10.0-fold in the aorta, and up to 30.0-fold in the liver (all P < 0. 01 vs. control). While both AT1RA (group 3) and hydralazine (group 4) prevented Ang II-induced elevation in blood pressure, the Ang II-dependent expression of PAI-1 mRNA was reduced by only AT1 receptor blockade. CONCLUSIONS: We conclude that in the rat, PAI-1 is induced in a variety of tissues by Ang II directly through the AT1 receptor, independent of its effects on blood pressure.

Angiotensin II↗
PubMed2000

Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo.

BACKGROUND: Aldosterone promotes nephrosclerosis in several rat models, whereas aldosterone receptor antagonism blunts the effect of activation of the renin-angiotensin-aldosterone system (RAAS) on nephrosclerosis, independent of effects on blood pressure. Based on recent findings linking activation of the RAAS with impaired fibrinolytic balance, we hypothesized that aldosterone induces sclerosis through effects on plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of plasminogen activation. METHODS: We examined the effect of aldosterone antagonism on the development of sclerosis and on renal PAI-1 expression following radiation injury in the rat. Following a single dose of 12 Gy to the kidneys, male Sprague-Dawley rats were treated with placebo, the aldosterone antagonist spironolactone (4.5 mg/day by time-release subcutaneous pellet), the angiotensin type 1 receptor antagonist L158-809 (AT1RA; 80 mg/L drinking water), or combined spironolactone and AT1RA. RESULTS: Rats treated with placebo developed significant proteinuria and nephrosclerosis 12 weeks following radiation associated with hypertension. Kidney PAI-1 mRNA expression was increased eightfold (P < 0.001 vs. nonradiated controls). Spironolactone alone had no effect on blood pressure (systolic blood pressure 149.0 +/- 5.4 mm Hg) compared with placebo (151.6 +/- 11.2 mm Hg, P = NS), whereas AT1RA alone (107.7 +/- 8.9 mm Hg, P = 0.013 vs. placebo) or in combination therapy (102.1 +/- 6.2 mm Hg, P = 0.001 vs. placebo) lowered blood pressure. Both the AT1RA and spironolactone decreased proteinuria following radiation (P < 0.001 vs. placebo for either drug), and the combination of AT1RA + spironolactone had a greater effect on proteinuria than spironolactone alone (P = 0.003). Aldosterone antagonism significantly decreased (P = 0.016 vs. placebo) and AT1RA virtually abolished (P = 0.001 vs. placebo) the development of sclerosis. Spironolactone significantly decreased PAI-1 mRNA expression in the kidneys of radiated animals (PAI-1 mRNA/GAPDH ratio 0.39 +/- 0.13 vs. placebo 0.84 +/- 0.05, P = 0.006), and there was a significant correlation between the degree of sclerosis and the level of PAI-1 immunostaining within individual rats (R2 = 0.97, P < 0.0001). CONCLUSION: This study is, to our knowledge, the first to demonstrate that aldosterone regulates PAI-1 expression in vivo, and supports the hypothesis that aldosterone induces renal injury through its effects on PAI-1 expression.

Aldosterone↗
PubMed2000

Regression of sclerosis in aging by an angiotensin inhibition-induced decrease in PAI-1.

BACKGROUND: Glomerular and vascular sclerosis increase with aging, and angiotensin inhibitors ameliorate progression of this injury. We investigated the potential for achieving regression of existing age-related sclerosis, and the mechanisms by which angiotensin type 1 receptor antagonist (AIIRA) may affect remodeling of this sclerosis. We focused on plasminogen activator inhibitor-1 (PAI-1) because it is directly induced by angiotensin, inhibits matrix degradation, and may thus be pivotal in remodeling. METHODS: Eighteen-month-old male Sprague-Dawley rats were treated with the AIIRA losartan (N = 8, 80 mg/L, dry weight), sacrificed at age 21 and 24 months, and compared with age-matched untreated controls (N = 15). Blood pressure and renal function were monitored, and morphological, biochemical, and molecular analyses were done on aorta and kidney. RESULTS: Body weight increased in both groups. Mean arterial pressure (MAP) and serum creatinine remained normal (24-month MAP 115 +/- 8 vs. 113 +/- 6 mm Hg, controls vs. AIIRA, P = NS). Aorta wall thickness ratio was reduced by AIIRA at 21 and 24 months vs. age-matched controls (21 months 0. 12 +/- 0.01 vs. 0.15 +/- 0.01, P = 0.006; 24 months 0.10 +/- 0.005 vs. 0.14 +/- 0.003, AIIRA vs. controls, respectively, P = 0.0027). The aorta wall thickness ratio after treatment with AIIRA for six months was even lower than that of 18-month control rats (P = 0.018). AIIRA reduced proteinuria versus age-matched control at 24 months (253 +/- 62 vs. 390 +/- 51 mg/24 h, P = 0.0017). AIIRA at 24 months decreased glomerulosclerosis versus age-matched control (sclerosis index, 0 to 4+ scale: 0.06 +/- 0.02 vs. 0.49 +/- 0.12, P = 0.0082) to levels even lower than the 18-month baseline (0.37 +/- 0.14, P = 0.014). Renal collagen content increased with aging and was decreased by AIIRA at 24 months (5.0 +/- 0.7 vs. 3.1 +/- 0.5% collagen, P < 0.05). Apoptosis, assessed by TUNEL, was increased in tubular and interstitial cells in aging and was reduced by AIIRA versus control and baseline, respectively (TUNEL scoring, AIIRA 24 months 0.33 +/- 0.16 vs. 1.06 +/- 0.23 and 0.80 +/- 0.05, P < 0.05). PAI-1 mRNA in kidney was decreased at 24 months in AIIRA versus age-matched controls (PAI-1/GAPDH density ratio: AIIRA 24 months 0. 34 +/- 0.05 vs. 24-month controls 0.99 +/- 0.05, P < 0.05). Increased glomerular PAI-1 immunostaining with aging was decreased by AIIRA at 24 months versus age-matched controls, even below baseline (staining score 0 to 4+, 0.57 +/- 0.15 vs. control 0.90 +/- 0.07, P < 0.05; baseline 1.05 +/- 0.02, P < 0.01). CONCLUSION: We conclude that AIIRA not only slows the progression of glomerular and vascular sclerosis in aging, but can also induce regression of these processes. The mechanisms appear to involve modulation of cortical cell turnover and inhibition of PAI-1 expression.

Aging↗