Role of purinergic signaling in murine models of diabetic nephropathy.

MAZZOCCO , YANINA L.; BERGERO, G; MALDIN, G; CANO, RC; AOKI, MP

Congreso; Reunión Conjunta SAIC SAI AAFE NANOMED. Noviembre 2021.; 2021

ROLE OF PURINERGIC SIGNALINGS IN MURINE MODELS OF DIABETIC NEPHROPATHY Yanina Luciana Mazzocco 1,2, Gastón Bergero 1,2, Juan Mladin3, Roxana Carolina Cano1;2, María Pilar Aoki 1,2 1. Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba. 2. Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI)-CONICET, Córdoba, Argentina. 3. Hospital Misericordia, Córdoba, Argentina.We have previously reported that during an inflammatory or infectious stimulus, cells sense the hypoxic environment and release to the extracellular milieu large amounts of ATP, which functions as a pro-inflammatory metabolite driving the nature of the immune response. The purinergic ectoenzymes CD39 and CD73, metabolize extracellular ATP into adenosine, an anti-inflammatory mediator. These purinergic pathways have been studied in the context of metabolic diseases related to kidney damage, but their role in the type II diabetes mellitus (T2DM) nephropathy have not been completely established.The objective of the present work was to study the role of CD73 in the development of diabetic nephropathy employing mice devoid of CD73 activity (CD73KO) and controls B6 (WT). To this aim, we developed two murine models of T2DM, feeding the mice with medium fat diet (17%) and water 20% fructose (model A) and high fat diet (60%) (model B) for 22 weeks, combined with a single dose of streptozotocin (65-100mg/kg). In both models, at the end of treatment, blood glucose levels were higher than 190mg/dl; but, in model A KO animals gained significantly less weight compared to the WT (p=0,0043). In model A, both mouse strains showed comparable renal damage parameters, such as a decrease in diuresis and a loss of more than 50% of glomerular filtration rate as well as significantly higher values of microalbuminuria (pWT=0,0327, pKO=0,0500), and plasma creatinine (pWT=0,0159, pKO=0,0159). In contrast, in model B, diabetic KO mice show signs of improvement with a significant correction of diuresis (p=0.0346), albuminuria (p=0.0303) and proteinuria (p=0.0043) compared to diabetic WT. Furthermore, plasma and urinary creatinine from diabetic KO mice did not show significant differences respect to healthy KO (p=0.556, p=0.9667). In conclusion, the results suggest that CD73 activity could have a protective role in the development of diabetic nephropathy in a diet dependent manner.