TY - JOUR
T1 - Monosodium urate contributes to retinal inflammation and progression of diabetic retinopathy
AU - Thounaojam, Menaka C.
AU - Montemari, Annalisa
AU - Powell, Folami L.
AU - Malla, Prerana
AU - Gutsaeva, Diana R.
AU - Bachettoni, Alessandra
AU - Ripandelli, Guido
AU - Repossi, Andrea
AU - Tawfik, Amany
AU - Martin, Pamela M.
AU - Facchiano, Francesco
AU - Bartoli, Manuela
N1 - Funding Information:
This work received financial support from the International Retinal Research Foundation (to M.B.) and from the National Institutes of Health National Eye Institute (R01-EY-022416 and R01-EY-028714 to M.B.).
Funding Information:
Acknowledgments. The authors acknowledge the excellent technical assistance of Dr. Jianghe Yuan (Medical College of Georgia, Augusta University, Augusta, GA). The authors also thank Giovanni Parisi (IRCCS Fodazione G.B. Bietti, Rome, Italy) for his technical assistance for the human studies and the Facility for Complex Protein Mixture (CPM) (Istituto Superiore di Sanità, Rome, Italy). Funding. This work received financial support from the International Retinal Research Foundation (to M.B.) and from the National Institutes of Health National Eye Institute (R01-EY-022416 and R01-EY-028714 to M.B.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. M.C.T. performed the experiments and developed the project. A.M. organized and performed the experiments with human samples. F.L.P. contributed to the in vivo experiments. P.M. participated in the in vitro and in vivo experiments. D.R.G. contributed to data analysis and manuscript preparation. A.B. analyzed human vitreous samples. G.R. provided the vitreous samples. A.R. provided the vitreous samples and clinical expertise for data analysis. A.T. performed and analyzed the FA data. P.M.M. contributed to data analysis and writing the manuscript. F.F. contributed to the realization of the human studies and data analysis. M.B. developed the idea, designed the studies described here, and provided financial support for their realization. M.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
PY - 2019
Y1 - 2019
N2 - We have investigated the contributing role of monosodium urate (MSU) to the pathological processes associated with the induction of diabetic retinopathy (DR). In human postmortem retinas and vitreous from donors with DR, we have found a significant increase in MSU levels that correlated with the presence of inflammatory markers and enhanced expression of xanthine oxidase. The same elevation in MSU levels was also detected in serum and vitreous of streptozotocin-induced diabetic rats (STZ-rats) analyzed at 8 weeks of hyperglycemia. Furthermore, treatments of STZ-rats with the hypouricemic drugs allopurinol (50 mg/kg) and benzbromarone (10 mg/kg) given every other day resulted in a significant decrease of retinal and plasma levels of inflammatory cytokines and adhesion factors, a marked reduction of hyperglycemia-induced retinal leukostasis, and restoration of retinal blood-barrier function. These results were associated with effects of the hypouricemic drugs on downregulating diabetes-induced levels of oxidative stress markers as well as expression of components of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome such as NLRP3, Tolllike receptor 4, and interleukin-1b. The outcomes of these studies support a contributing role of MSU in diabetes-induced retinal inflammation and suggest that asymptomatic hyperuricemia should be considered as a risk factor for DR induction and progression.
AB - We have investigated the contributing role of monosodium urate (MSU) to the pathological processes associated with the induction of diabetic retinopathy (DR). In human postmortem retinas and vitreous from donors with DR, we have found a significant increase in MSU levels that correlated with the presence of inflammatory markers and enhanced expression of xanthine oxidase. The same elevation in MSU levels was also detected in serum and vitreous of streptozotocin-induced diabetic rats (STZ-rats) analyzed at 8 weeks of hyperglycemia. Furthermore, treatments of STZ-rats with the hypouricemic drugs allopurinol (50 mg/kg) and benzbromarone (10 mg/kg) given every other day resulted in a significant decrease of retinal and plasma levels of inflammatory cytokines and adhesion factors, a marked reduction of hyperglycemia-induced retinal leukostasis, and restoration of retinal blood-barrier function. These results were associated with effects of the hypouricemic drugs on downregulating diabetes-induced levels of oxidative stress markers as well as expression of components of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome such as NLRP3, Tolllike receptor 4, and interleukin-1b. The outcomes of these studies support a contributing role of MSU in diabetes-induced retinal inflammation and suggest that asymptomatic hyperuricemia should be considered as a risk factor for DR induction and progression.
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U2 - 10.2337/db18-0912
DO - 10.2337/db18-0912
M3 - Article
C2 - 30728185
AN - SCOPUS:85065109410
VL - 68
SP - 1014
EP - 1025
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 5
ER -