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Biomedical subjects

Agnes B Fogo

Publications and source records attributed to Agnes B Fogo.

At least 73 records · Page 4Linked to original sources
PubMed2003

Renal fibrosis: not just PAI-1 in the sky.

A delicate balance exists between ECM synthesis and degradation such that interruption of the corresponding pathways results in increased plasminogen activator inhibitor-1 (PAI-1), pathological matrix accumulation, and glomerulosclerosis. A new study demonstrates that therapy with a mutant PAI-1 increases matrix turnover and reduces glomerulosclerosis by competing with endogenous PAI-1, suggesting therapeutic utility in the treatment of fibrotic renal disease.

Animals↗
PubMed2002

Potential roles of plasminogen activator system in coronary vascular remodeling induced by long-term nitric oxide synthase inhibition.

Recent studies have indicated that a number of factors contribute to the pathophysiology in response to nitric oxide synthase (NOS) inhibition. We previously demonstrated that plasminogen activator inhibitor-1 deficient (PAI-1-/-) mice are protected against hypertension and perivascular fibrosis induced by relatively short-term NOS inhibition. In this study, we compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis induced by long-term treatment with N(omega)-nitro- L -arginine methyl ester (L -NAME) in wild type (WT), PAI-1(-/-) and tissue-type plasminogen activator deficient (t-PA-/-) mice. After initiating L -NAME, systolic blood pressure increased in all groups at 2 weeks. Over a 16 week study period, systolic blood pressure increased to 143+/-3 mmHg (mean+/-SEM) in WT animals, 139+/-2 in t-PA-/- mice vs 129+/-2 in PAI-1-/- mice (P < 0.01). Coronary perivascular fibrosis increased in L -NAME-treated WT and t-PA(-/-) mice compared to each control group (P<0.01 in WT, P<0.05 in t-PA-/-), while PAI-1-/- mice were protected against fibrosis induced by L -NAME. t-PA deficiency did not accentuate the vascular pathology or the changes in blood pressure. In situ zymography demonstrated augmented gelatinolytic activity in PAI-1-/- mice at baseline, suggesting that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. Plasma TGF-beta1 levels increased in L -NAME-treated WT and PAI-1-/- mice (P < 0.01), but not in L -NAME-treated t-PA-/- mice. These findings support the hypothesis that the plasminogen activator system protects against the structural vascular changes induced by long-term NOS inhibition. While PAI-1 deficiency protects against L -NAME-induced hypertension and perivascular fibrosis, t-PA deficiency does not exacerbate the vascular pathology or hypertension.

Animals↗
PubMed2002

Microangiopathic injury and augmented PAI-1 in human diabetic nephropathy.

BACKGROUND: Microvascular injury and mesangial dysfunction contribute to the pathogenesis of diabetic glomerulosclerosis. We investigated the extent of microvascular injury characterized by fragmented red blood cells (RBCs) in the mesangium of glomeruli in diabetic nephropathy, and its clinicopathologic significance. We also investigated the possible contributions of plasminogen activator inhibitor-1 (PAI-1), which has been implicated in thrombosis and sclerosis, and the novel steroid receptor superfamily member, peroxisome proliferator-activated receptorgamma (PPARgamma), implicated in monocyte-foamy macrophage transformation in atherosclerosis and improved insulin responsiveness in diabetes. METHODS: Sixty-four diabetic nephropathy (DN) cases in our renal biopsy files at VUMC, diagnosed between 1997 and 1999, were reviewed. Patients were classified based on the presence or absence of fragmented RBCs in the mesangium (M+, M-). PAI-1 and PPARgamma immunostaining was performed with double staining for the macrophage marker CD68. RESULTS: M+ lesions were present in 21.9% of cases, and in positive cases, involved on average 10.2 +/- 2.1% of glomeruli. M+ patients were 40- to 78-years-old (mean +/- SD, 60.4 +/- 9.8), the female/male ratio was 2.5, and the white/black ratio was 6. In M-, the patients' ages ranged from 29 to 81 years (57.6 +/- 13.3, P = NS vs. M+), the female/male ratio was 0.5 (P < 0.05 vs. M+), and the white/black ratio was 2.3 (P = 0.1 vs. M+). Mean 24-hour urine protein in M+ was 9.9 +/- 13.6 g/24 h, versus 4.0 +/- 2.8 g/24 h in M- (P < 0.05). The fragmented RBCs in M+ cases localized exclusively within Kimmelstiel-Wilson nodules. PAI-1 and PPARgamma immunostaining was increased in areas of sclerosis in arteries and glomeruli, with expression of both in glomerular mesangial, parietal and visceral epithelial cells. Infiltrating macrophages in glomeruli were PPARgamma negative, contrasting positivity in macrophages in control cases of carotid artery plaque and in renal interstitial macrophages. The Kimmelstiel-Wilson nodules in M+ patients showed increased PAI-1 staining. CONCLUSIONS: Mesangial RBC fragments are indicative of microvascular injury and mesangiolysis in DN and are associated with worse proteinuria, and possible worse prognosis. Possible pathogenic mechanisms involve the fibrinolytic/proteolytic system and locally activated PAI-1.

Aged↗
PubMed2002

Hypertensive nephrosclerosis in African Americans versus Caucasians.

BACKGROUND: Extensive global glomerulosclerosis (GS) has been reported in African Americans with hypertension and renal insufficiency, far exceeding that in Caucasians. To assess and compare severity and phenotype of injury in biopsied African Americans and Caucasians who morphologically had hypertensive nephrosclerosis, we performed a retrospective biopsy study. METHODS: All renal biopsies with a histological diagnosis of hypertensive nephrosclerosis from the last 11 years were identified from our clinical files. Lesions of global and segmental sclerosis, interstitial fibrosis and vascular sclerosis were semiquantitatively analyzed as percent involved, or on a 0 to 3 scale, respectively. The phenotypes of global glomerulosclerosis also were categorized as either the solidified (that is, the entire tuft is solidified) or the obsolescent type (that is, Bowman's space is occupied by collagenous material and the tuft is retracted). RESULTS: Sixty-two patients (19 African Americans, 43 Caucasians) were included in the study. At biopsy, African Americans were younger than Caucasians with higher serum creatinine, but no difference in proteinuria or mean arterial pressure (MAP). African Americans had a marked increase in the solidified form of GS (25 +/- 6 in African Americans vs. 8 +/- 2% in Caucasians, P < 0.01). This extensive solidification of glomeruli was associated with segmental sclerosis in African Americans (38 +/- 10%), contrasting low prevalence of solidified GS in Caucasians with segmental sclerosis (10 +/- 3%, P < 0.05) and in African Americans without segmental sclerosis (10 +/- 4%, P < 0.05). African Americans with segmental sclerosis were younger and clinically expressed a more severe renal disease than Caucasians with this lesion. Interstitial fibrosis was greater in African Americans than in Caucasians (54 +/- 6 vs. 33 +/- 3%, P < 0.01) and correlated with proteinuria and serum creatinine levels, especially in African Americans, and also with GS. Vascular sclerosis was worse in African Americans than in Caucasians (0.96 +/- 0.04 vs. 0.77 +/- 0.08 score, P < 0.05) and did not correlate with GS. By modeling, neither MAP nor age was useful in predicting any morphological lesions and proteinuria accounted only minimally for the variability of GS. CONCLUSIONS: Blood pressure levels and proteinuria did not account for morphological lesions, suggesting other factors (such as genetic factors, microvascular disease) may play a role. The phenotype of GS differs in biopsied African Americans versus Caucasians with hypertensive nephrosclerosis, with a marked increase in the solidified form of GS in African Americans. The association of extensive solidified GS with segmental sclerosis lesions in African Americans, but not in Caucasians, suggests different mechanisms may contribute to the development and progression of sclerosis in these two patient groups.

Adult↗