Aldosterone and TGF-β<sub>1</sub>synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells

Huang, Wei; Xu, Chunli; Kahng, Kyoung Won; Noble, Nancy A.; Border, Wayne A.; Huang, Yufeng

doi:10.1152/ajprenal.00017.2008

Cited by 59 publications

(43 citation statements)

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“…Such observations may be explained by other Gal-3-independent mechanisms of fibrosis, known to be promoted by aldosterone, such as the induction of oxidative stress, 9 intracellular calcium accumulation, 27 or the increase in plasminogen activator inhibitor type 1. 28 Furthermore, cardiac expression and secretion of Gal-3 may be induced by other factors independent from MR activation, as ischemia and proinflammatory stimuli (Figure 7). …”

Section: Discussionmentioning

confidence: 99%

Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice

et al. 2016

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Abstract-Galectin-3 (Gal-3) is involved in inflammation, fibrogenesis, and cardiac remodeling. Previous evidence shows that Gal-3 interacts with aldosterone in promoting macrophage infiltration and vascular fibrosis and that Gal-3 genetic and pharmacological inhibition prevents remodeling in a pressure-overload animal model of heart failure. We aimed to explore the contribution of Gal-3 and aldosterone in mechanisms leading to heart failure in a murine model. Male mice with cardiac-specific hyperaldosteronism underwent isoproterenol subcutaneous injections, to be then randomized to receive placebo, a Gal-3 inhibitor (modified citrus pectin [MCP]), an aldosterone antagonist (potassium canrenoate), or MCP+canrenoate for 14 days. Isoproterenol induced a rapid and persistent decrease in left ventricular fractional shortening (−20% at day 14); this was markedly improved by treatment with either MCP or canrenoate (both P<0.001 versus placebo). MCP and canrenoate also reduced cardiac hypertrophy and fibrosis and the expression of genes involved in fibrogenesis (Coll-1 and Coll-3) and macrophage infiltration (CD-68 and MCP-1). After isoproterenol, Gal-3 gene expression (P<0.05 versus placebo) and protein levels (−61% and −69% versus placebo) were decreased by both canrenoate and MCP. The combined use of antagonists of Gal-3 and aldosterone resulted in more pronounced effects on cardiac hypertrophy, inflammation, and fibrosis, when compared with either MCP or canrenoate alone. Inhibition of Gal-3 and aldosterone can reverse isoproterenol-induced left ventricular dysfunction, by reducing myocardial inflammation and fibrogenesis. Gal-3 likely participates in mechanisms of aldosterone-mediated myocardial damage in a heart failure murine model with cardiac hyperaldosteronism. Gal-3 inhibition may represent a new promising therapeutic option in heart failure.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice

et al. 2016

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“…Furthermore, the role of Rho-kinase in aldosterone-induced renal cell injury is under investigation. The roles of other factors including transforming growth factor-β, plasminogen activator inhibitor type 1, and osteopontin in mediating renal fibroblast proliferation, collagen synthesis, or matrix degradation have also been indicated by recent studies (45,46).…”

Section: Renal Cell Injury Induced By Aldosterone and Its Possible Mementioning

confidence: 96%

Possible Underlying Mechanisms Responsible for Aldosterone and Mineralocorticoid Receptor–Dependent Renal Injury

et al. 2008

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Abstract. There is increasing evidence indicating the roles of aldosterone and mineralocorticoid receptor (MR) in the pathogenesis of renal injury. In rats, chronic treatment with aldosterone and salt results in severe proteinuria and renal tissue injury, characterized by glomerulosclerosis and tubulointerstitial fibrosis. Aldosterone-induced renal tissue injury is associated with increases in reactive oxygen species (ROS) levels and activation of mitogen-activated protein kinases (MAPKs) or Rho-kinase. Treatment with a selective MR antagonist, eplerenone, prevents aldosterone-induced increases in ROS levels and MAPK activity and ameliorates renal injury. In vitro studies have revealed that MR is highly expressed in glomerular mesangial cells (RMCs), podocytes, and renal interstitial fibroblasts. In these renal cells, aldosterone induces cellular injury through NADPH oxidase-dependent ROS production and activation of MAPKs or Rhokinase. Such aldosterone-induced renal cellular injury is markedly attenuated by treatment with eplerenone. These data suggest that aldosterone induces renal injury via activation of MR through mechanisms that cannot be simply explained by changes in blood pressure. In this review, we summarized recent findings on the roles of aldosterone and MR in the pathogenesis of renal injury with particular emphasis on potential underlying mechanisms.

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“…Reduction of PAI-1 levels in rimonabant-treated cp/cp rats may indicate an improvement in the prothrombotic status and is consistent with reduced glomerular sclerosis. We know that glomerular sclerosis is associated with accumulation of extracellular matrix, and this is related to increased concentration of PAI-1 (19,20). Thus, in the presence of an inflammatory status (such as atherosclerosis), the reduction of PAI-1 activity seen in the rimonabant-treated cp/cp rat represents an important therapeutic marker (20) of reduced renal dysfunction.…”

Section: Rimonabant and Proinflammationmentioning

confidence: 99%

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

Russell

Kelly

Diané

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Vine DF, Proctor SD. Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cp rat model of prediabetic metabolic syndrome. Am J Physiol Gastrointest Liver Physiol 299: G507-G516, 2010. First published May 27, 2010 doi:10.1152/ajpgi.00173.2010 is a specific antagonist of the cannabinoid-1 receptor. Activation of the receptor initiates multiple effects on central nervous system function, metabolism, and body weight. The hypothesis that rimonabant has protective effects against vascular disease associated with the metabolic syndrome was tested using JCR:LA-cp rats. JCR:LA-cp rats are obese if they are cp/cp, insulin resistant, and exhibit associated micro-and macrovascular disease with end-stage myocardial and renal disease. Treatment of obese rats with rimonabant (10 mg·kg Ϫ1 ·day Ϫ1 , 12-24 wk of age) caused transient reduction in food intake for 2 wk, without reduction in body weight. However, by 4 wk, there was a modest, sustained reduction in weight gain. Glycemic control improved marginally compared with controls, but at the expense of increased insulin concentration. In contrast, rimonabant normalized fasting plasma triglyceride and reduced plasma plasminogen activator inhibitor-1 and acute phase protein haptoglobin in cp/cp rats. Furthermore, these changes were accompanied by reduced postprandial intestinal lymphatic secretion of apolipoprotein B48, cholesterol, and haptoglobin. While macrovascular dysfunction and ischemic myocardial lesion frequency were unaffected by rimonabant treatment, both microalbuminuria and glomerular sclerosis were substantially reduced. In summary, rimonabant has a modest effect on body weight in freely eating obese rats and markedly reduces plasma triglyceride levels and microvascular disease, in part due to changes in intestinal metabolism, including lymphatic secretion of apolipoprotein B48 and haptoglobin. We conclude that rimonabant improves renal disease and intestinal lipid oversecretion associated with an animal model of the metabolic syndrome that appears to be independent of hyperinsulinemia or macrovascular dysfunction. metabolic syndrome; chylomicron overproduction; inflammation; microalbuminuria; glomerular sclerosis; plasminogen activator inhibitor-1; apolipoprotein B48 EXCESSIVE WEIGHT GAIN, PARTICULARLY in the form of abdominal (visceral) adipose tissue, is a major public health problem in prosperous societies worldwide (16,65). The resultant abdominal obesity has driven a developing epidemic of prediabetic insulin resistance and cluster of associated metabolic abnormalities that are termed the metabolic syndrome (9, 35). Insulin resistance leads to chronic hyperinsulinemia and has been implicated as a major determinant of early development of macro-and microvasculopathy, including atherosclerosis, ischemic cardiovascular disease (CVD), and renal damage, which are strongly associated with the metabolic syndrome (9, 26). The contribution of the metabolic syndrome to the development of cardiovascular and re...

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Aldosterone and TGF-β₁synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells

Cited by 59 publications

References 57 publications

Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice

Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice

Possible Underlying Mechanisms Responsible for Aldosterone and Mineralocorticoid Receptor–Dependent Renal Injury

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

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Aldosterone and TGF-β1synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells

Cited by 59 publications

References 57 publications

Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice

Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice

Possible Underlying Mechanisms Responsible for Aldosterone and Mineralocorticoid Receptor–Dependent Renal Injury

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

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Aldosterone and TGF-β₁synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells