Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement?

Ravarotto, Verdiana; Simioni, Francesca; Carraro, Gianni; Bertoldi, Giovanni; Pagnin, Elisa; Calò, Lorenzo A.

doi:10.3390/jcm7110409

Cited by 20 publications

(19 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recent data highlighted the role of oxidative stress in FD pathophysiology. FD patients present high lipid and protein oxidative damage, decreased antioxidant defences and increased inflammatory biomarkers and cytokines [3][4][5][6][7][8][9][10]. Excess intracellular Gb3 induces oxidative stress and up-regulates the expression of cellular adhesion molecules in vascular endothelial cells [5].…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress biomarkers in Fabry disease: is there a room for them?

et al. 2020

View full text Add to dashboard Cite

Background Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression. Methods We have examined oxidative stress biomarkers [Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups] in blood samples from 60 patients and 77 healthy controls. Results AOPP levels were higher in patients than in controls (p < 0.00001) and patients presented decreased levels of antioxidant defences (FRAP and thiols) with respect to controls (p < 0.00001). In a small group of eight treatment-naïve subjects with FD-related mutations, we found altered levels of oxidative stress parameters and incipient signs of organ damage despite normal lyso-Gb3 levels. Conclusions Oxidative stress occurs in FD in both treated and naïve patients, highlighting the need of further research in oxidative stress-targeted therapies. Furthermore, we found that oxidative stress biomarkers may represent early markers of disease in treatment-naïve patients with a potential role in helping interpretation of FD-related mutations and time to treatment decision.

show abstract

Section: Introductionmentioning

confidence: 99%

Oxidative stress biomarkers in Fabry disease: is there a room for them?

et al. 2020

View full text Add to dashboard Cite

show abstract

“…First, considering that AngII produces damage in the kidney, we identified the time point when renal damage turns irreversible, which resulted in be after 4 weeks of treatment with AngII since SBP, inflammation, OS, fibrosis, the amount of Cx43 and p-MYPT-1 remained high even after 2 weeks of AngII withdrawal. This could be explained by renal cell dysfunction that develops by the initial action of AngII and establishes interconnections between OS, inflammation, and fibrosis [40]. Although The half-life of bioactive peptides such as AngII is likely to be about a few hours [41], these interconnections coexist and communicate with each other independent of AngII, thereby exacerbating the processes underpinning these different entities with the end result of high morbidity and mortality in this model of kidney damage [40].…”

Section: Discussionmentioning

confidence: 99%

“…This could be explained by renal cell dysfunction that develops by the initial action of AngII and establishes interconnections between OS, inflammation, and fibrosis [40]. Although The half-life of bioactive peptides such as AngII is likely to be about a few hours [41], these interconnections coexist and communicate with each other independent of AngII, thereby exacerbating the processes underpinning these different entities with the end result of high morbidity and mortality in this model of kidney damage [40]. Also, we found an increase in kidney macrophage infiltration (ED-1) and renal amounts of IL-1β in response to AngII, indicating the presence of an inflammatory response mediated by the innate immune system.…”

Section: Discussionmentioning

confidence: 99%

Role of a RhoA/ROCK-Dependent Pathway on Renal Connexin43 Regulation in the Angiotensin II-Induced Renal Damage

Gómez

Velarde

Sáez

2019

IJMS

View full text Add to dashboard Cite

In various models of chronic kidney disease, the amount and localization of Cx43 in the nephron is known to increase, but the intracellular pathways that regulate these changes have not been identified. Therefore, we proposed that: “In the model of renal damage induced by infusion of angiotensin II (AngII), a RhoA/ROCK-dependent pathway, is activated and regulates the abundance of renal Cx43”. In rats, we evaluated: 1) the time-point where the renal damage induced by AngII is no longer reversible; and 2) the involvement of a RhoA/ROCK-dependent pathway and its relationship with the amount of Cx43 in this irreversible stage. Systolic blood pressure (SBP) and renal function (urinary protein/urinary creatinine: Uprot/UCrea) were evaluated as systemic and organ outcomes, respectively. In kidney tissue, we also evaluated: 1) oxidative stress (amount of thiobarbituric acid reactive species), 2) inflammation (immunoperoxidase detection of the inflammatory markers ED-1 and IL-1β), 3) fibrosis (immune detection of type III collagen; Col III) and 4) activity of RhoA/ROCK (amount of phosphorylated MYPT1; p-MYPT1). The ratio Uprot/UCrea, SBP, oxidative stress, inflammation, amount of Cx43 and p-MYPT1 remained high 2 weeks after suspending AngII treatment in rats treated for 4 weeks with AngII. These responses were not observed in rats treated with AngII for less than 4 weeks, in which all measurements returned spontaneously close to the control values after suspending AngII treatment. Rats treated with AngII for 6 weeks and co-treated for the last 4 weeks with Fasudil, an inhibitor of ROCK, showed high SBP but did not present renal damage or increased amount of renal Cx43. Therefore, renal damage induced by AngII correlates with the activation of RhoA/ROCK and the increase in Cx43 amounts and can be prevented by inhibitors of this pathway.

show abstract

“…First, considering that AngII produces damage in the kidney, we identified the time point when renal damage turns irreversible, which resulted to be after 4 weeks of treatment with AngII since SBP, inflammation, OS, fibrosis, the amount of Cx43 and p-MYPT-1 remained high even after 2 weeks of AngII withdrawal. This could be explained by renal cell dysfunction that develops by the initial action of AngII and establishes interconnections between OS, inflammation, and fibrosis [40]. Although The half-life of bioactive peptides such as AngII is likely to be about a few hours [41], these interconnections coexist and communicate with each other independent of AngII, thereby exacerbating the processes underpinning these different entities with the end result of high morbidity and mortality in this model of kidney damage [40].…”

Section: Discussionmentioning

confidence: 99%

Role of a RhoA/ROCK-Dependent Pathway on Renal Connexin43 Regulation in the Angiotensin II-Induced Renal Damage

Gómez

Velarde

Sáez

2019

Preprint

View full text Add to dashboard Cite

In various models of chronic kidney disease, the amount and localization of Cx43 in the nephron is known to increase, but the intracellular pathways that regulate these changes have not been identified. Therefore, we proposed that: "In the model of renal damage induced by infusion of angiotensin II (AngII), a RhoA/ROCK-dependent pathway, is activated and regulates the abundance of renal Cx43". In rats, we evaluated: 1) the time-point where the renal damage induced by AngII is no longer reversible; and 2) the involvement of a RhoA/ROCK-dependent pathway and its relationship with the amount of Cx43 in this irreversible stage. Systolic blood pressure (SBP) and renal function (urinary protein/urinary creatinine: Uprot/UCrea) were evaluated as systemic and organ outcomes, respectively. In kidney tissue, we also evaluated: 1) oxidative stress (amount of thiobarbituric acid reactive species), 2) inflammation (immunoperoxidase detection of the inflammatory markers ED-1 and IL-1β), 3) fibrosis (immune detection of type III collagen; Col III) and 4) activity of RhoA/ROCK (amount of phosphorylated MYPT1; p-MYPT1). The ratio Uprot/UCrea, SBP, oxidative stress, inflammation, amount of Cx43 and p-MYPT1 remained high 2 weeks after suspending AngII treatment in rats treated for 4 weeks with AngII. These responses were not observed in rats treated with AngII for less than 4 weeks, in which all measurements returned spontaneously close to the control values after suspending AngII treatment. Rats treated with AngII for 6 weeks and co-treated for the last 4 weeks with Fasudil, an inhibitor of ROCK, showed high SBP but did not present renal damage or increased amount of renal Cx43. Therefore, renal damage induced by AngII correlates with the activation of RhoA/ROCK and the increase in Cx43 amounts and can be prevented by inhibitors of this pathway.

show abstract

Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement?

Cited by 20 publications

References 36 publications

Oxidative stress biomarkers in Fabry disease: is there a room for them?

Oxidative stress biomarkers in Fabry disease: is there a room for them?

Role of a RhoA/ROCK-Dependent Pathway on Renal Connexin43 Regulation in the Angiotensin II-Induced Renal Damage

Role of a RhoA/ROCK-Dependent Pathway on Renal Connexin43 Regulation in the Angiotensin II-Induced Renal Damage

Contact Info

Product

Resources

About