Systemic Inflammasome Biomarkers as Predictors of Diabetic Retinopathy Progression: Evidence from a Pilot Study

Kuo, Charisse Y.-J.; Rupenthal, Ilva D.; Booth, Michael; Murphy, Rinki; Mugisho, Odunayo O.

doi:10.3390/futurepharmacol3030039

Cited by 3 publications

(1 citation statement)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A systematic literature review showed that DR progression correlates with increasing levels of inflammasome biomarkers in both the vitreous and serum, suggesting serum inflammasome levels can potentially be used to predict DR progression [42]. Moreover, a clinical pilot study showed that in a cohort of patients who have undergone bariatric surgery, the group that progressed in DR 1 year post-surgery had a significant increase in serum IL-18, one of the activated inflammasome biomarkers, compared to those who regressed or remained stable [43]. Collectively, these studies strongly suggest that the NLRP3 inflammasome becomes increasingly activated as DR becomes more severe.…”

Section: Clinical Evidence Of the Nlrp3 Inflammasome In Dr Progressionmentioning

confidence: 99%

Future Therapeutics: Targeting the NLRP3 Inflammasome Pathway to Manage Diabetic Retinopathy Development and Progression

Kuo,

Rupenthal,

Murphy

et al. 2024

IJTM

Self Cite

View full text Add to dashboard Cite

While existing local therapies partially restore vision loss from diabetic retinopathy (DR), there is currently no reliable treatment to prevent the onset or stop the progression of the disease. This review seeks to explore the inflammatory molecular mechanisms underpinning DR pathogenesis, which have not been targeted by current interventions. Specifically, this review explores the role of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) inflammasome in DR onset and progression. Evidence through clinical trials has begun to note that specific drugs (fenofibrate, metformin) appear effective in slowing DR progression independent of lipid or glucose-lowering, respectively, suggesting that other mechanisms are at play. Novel therapeutics that inhibit the activation of the NLRP3 inflammasome pathway may provide a novel treatment for halting DR progression.

show abstract

Section: Clinical Evidence Of the Nlrp3 Inflammasome In Dr Progressionmentioning

confidence: 99%

Future Therapeutics: Targeting the NLRP3 Inflammasome Pathway to Manage Diabetic Retinopathy Development and Progression

Kuo,

Rupenthal,

Murphy

et al. 2024

IJTM

Self Cite

View full text Add to dashboard Cite

show abstract

Weight loss, bariatric surgery, and novel antidiabetic drugs effects on diabetic retinopathy: a review

Perez,

Neag,

Sridhar

et al. 2024

Current Opinion in Ophthalmology

View full text Add to dashboard Cite

Purpose of review Diabetic retinopathy (DR) is a leading cause of visual impairment, and the increasing prevalence of diabetes and obesity will impact rates of visual impairment moving forward. Our review aims to synthesize the current body of evidence regarding the impact of lifestyle interventions, such as weight loss, bariatric surgery, and novel antidiabetic drugs, on DR. Recent findings Literature review revealed insufficient evidence regarding the impact of weight loss on DR. Preoperative DR patients undergoing bariatric surgery were found to have similar short-term chances of improvement or worsening DR. Progression of DR with glucagon-like peptide 1 receptor agonists treatments appears unrelated to specific drugs and was also observed with traditional antidiabetic medications. Summary Rapidly correcting HbA1c levels (≥2%) can paradoxically lead to early worsening DR. Patients considering weight loss, bariatric surgery, and novel antidiabetic drugs should be aware of the potential for DR progression, but they should not be discouraged, as achieving glycemic control is essential for reducing long-term morbidity and mortality from other diabetes-related complications. It is advisable to conduct a baseline retinal examination before treatment and continue monitoring during therapy. Further research is needed to understand the long-term effects of these treatments on DR.

show abstract

Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease

Cliff,

Squires,

Hills

2024

Cell Commun Signal

View full text Add to dashboard Cite

Background Accompanied by activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, aberrant connexin 43 (Cx43) hemichannel-mediated ATP release is situated upstream of inflammasome assembly and inflammation and contributes to multiple secondary complications of diabetes and associated cardiometabolic comorbidities. Evidence suggests there may be a link between Cx43 hemichannel activity and inflammation in the diabetic kidney. The consequences of blocking tubular Cx43 hemichannel-mediated ATP release in priming/activation of the NLRP3 inflammasome in a model of diabetic kidney disease (DKD) was investigated. We examined downstream markers of inflammation and the proinflammatory and chemoattractant role of the tubular secretome on macrophage recruitment and activation. Methods Analysis of human transcriptomic data from the Nephroseq repository correlated gene expression to renal function in DKD. Primary human renal proximal tubule epithelial cells (RPTECs) and monocyte-derived macrophages (MDMs) were cultured in high glucose and inflammatory cytokines as a model of DKD to assess Cx43 hemichannel activity, NLRP3 inflammasome activation and epithelial-to-macrophage paracrine-mediated crosstalk. Tonabersat assessed a role for Cx43 hemichannels. Results Transcriptomic analysis from renal biopsies of patients with DKD showed that increased Cx43 and NLRP3 expression correlated with declining glomerular filtration rate (GFR) and increased proteinuria. In vitro, Tonabersat blocked glucose/cytokine-dependant increases in Cx43 hemichannel-mediated ATP release and reduced expression of inflammatory markers and NLRP3 inflammasome activation in RPTECs. We observed a reciprocal relationship in which NLRP3 activity exacerbated increased Cx43 expression and hemichannel-mediated ATP release, events driven by nuclear factor kappa-B (NFκB)-mediated priming and Cx43 hemichannel opening, changes blocked by Tonabersat. Conditioned media (CM) from RPTECs treated with high glucose/cytokines increased expression of inflammatory markers in MDMs, an effect reduced when macrophages were pre-treated with Tonabersat. Co-culture using conditioned media from Tonabersat-treated RPTECs dampened macrophage inflammatory marker expression and reduced macrophage migration. Conclusion Using a model of DKD, we report for the first time that high glucose and inflammatory cytokines trigger aberrant Cx43 hemichannel activity, events that instigate NLRP3-induced inflammation in RPTECs and epithelial-to-macrophage crosstalk. Recapitulating observations previously reported in diabetic retinopathy, these data suggest that Cx43 hemichannel blockers (i.e., Tonabersat) may dampen multi-system damage observed in secondary complications of diabetes.

show abstract

Systemic Inflammasome Biomarkers as Predictors of Diabetic Retinopathy Progression: Evidence from a Pilot Study

Cited by 3 publications

References 46 publications

Future Therapeutics: Targeting the NLRP3 Inflammasome Pathway to Manage Diabetic Retinopathy Development and Progression

Future Therapeutics: Targeting the NLRP3 Inflammasome Pathway to Manage Diabetic Retinopathy Development and Progression

Weight loss, bariatric surgery, and novel antidiabetic drugs effects on diabetic retinopathy: a review

Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease

Contact Info

Product

Resources

About