RESUMO
Recent studies implicate neuronal guidance molecules in the orchestration of inflammatory events. For example, previous studies demonstrate a functional role for netrin-1 in attenuating acute kidney injury. Here, we hypothesized a kidney-protective role for netrin-1 during chronic kidney disease, such as occurs during diabetic nephropathy. To study the role of netrin-1 during diabetic nephropathy, we induced diabetes in mice at the age of 8 weeks by streptocotozin (STZ) treatment. Sixteen weeks after STZ treatment, we examined the kidneys. Initial studies in wild-type mice demonstrated robust induction of renal, urinary, and plasma netrin-1 protein levels during diabetic nephropathy. Subsequent genetic studies in mice with partial netrin-1 deficiency (Ntrn1(+/-) mice) revealed a more severe degree of diabetic nephropathy, including more severe loss of kidney function (albuminuria, glomerular filtration rate, histology). We subsequently performed pharmacologic studies with recombinant netrin-1 treatment given continuously via osmotic pump. Indeed, netrin-1 treatment was associated with attenuated albuminuria and improved histologic scores for diabetic nephropathy compared to controls. Consistent with previous studies implicating purinergic signaling in netrin-1-elicited tissue protection, mice deficient in the Adora2b adenosine receptor were not protected. Taken together, these studies demonstrate a functional role for endogenous netrin-1 in attenuating diabetic kidney disease.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Albuminúria/metabolismo , Animais , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/farmacologia , Netrina-1 , Receptor A2B de Adenosina/genética , Proteínas Recombinantes/farmacologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/farmacologiaRESUMO
UNLABELLED: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality of hepatic surgery and during liver transplantation. Previous studies implicated extracellular adenosine signaling in liver protection. Based on the notion that extracellular adenosine signaling is terminated by uptake from the extracellular towards the intracellular compartment by way of equilibrative nucleoside transporters (ENTs), we hypothesized a functional role of ENTs in liver protection from ischemia. During orthotopic liver transplantation in humans, we observed higher expressional levels of ENT1 than ENT2, in conjunction with repression of ENT1 and ENT2 transcript and protein levels following warm ischemia and reperfusion. Treatment with the pharmacologic ENT inhibitor dipyridamole revealed elevations of hepatic adenosine levels and robust liver protection in a murine model of liver ischemia and reperfusion. Studies in gene-targeted mice for Ent1 or Ent2 demonstrated selective protection from liver injury in Ent1(-/-) mice. Treatment with selective adenosine receptor antagonists indicated a contribution of Adora2b receptor signaling in ENT-dependent liver protection. CONCLUSION: These findings implicate ENT1 in liver protection from ischemia and reperfusion injury and suggest ENT inhibitors may be of benefit in the prevention or treatment of ischemic liver injury.