Protective role for netrin-1 during diabetic nephropathy

Abstract

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 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.

Netrin-1 Promotes Epithelial Sodium Channel-Mediated Alveolar Fluid Clearance via Activation of the Adenosine 2B Receptor in Lipopolysaccharide-Induced Acute Lung Injury

“…Rosenberger et al [38] first revealed that a hypoxia-induced increase in netrin-1 has anti-inflammatory effects exerted via an interaction with A2BAR expressed on polymorphonuclear neutrophils (polymorphonuclear leucocytes) to attenuate cytokine production and neutrophil transepithelial migration. Supporting this discovery, an anti-inflammatory effect of netrin-1 has also been observed in models of acute experimental colitis [39], acute kidney injury [40], and diabetic nephropathy [41]. Netrin-1 was robustly induced due to hypoxia in the above conditions and directly limited the trafficking of neutrophils to ameliorate inflammation through A2BAR.…”

“…Netrin-1 was robustly induced due to hypoxia in the above conditions and directly limited the trafficking of neutrophils to ameliorate inflammation through A2BAR. In mice with partial netrin-1 deficiency, the conditions were more severe and exogenous netrin-1 alleviated the development of these diseases [39,40,41]. Meanwhile, a lack of functional A2BAR was proven to abrogate the protective effect of netrin-1 in these models, emphasizing the necessary role of A2BAR in these processes.…”

Swerving away from diabetic nephropathy by means of divine guidance

“…The results suggest a functional role for endogenous netrin-1 in attenuating diabetic renal disease. The studies of Mohamed et al [7] and Tak and colleagues [8] seem quite complimentary. "One swallow does not make a summer," but two swallows probably fly in the right direction.…”

“…Confirmatory information from an independent source is helpful, particularly if the model is a different one and the findings are not quite the same. Tak et al [8] investigated a protective role for netrin-1 during diabetic nephropathy. They studied the role of netrin-1 during diabetic nephropathy, by inducing diabetes in mice with streptozotocin treatment.…”

“…Ntrn1+ /− mice developed more severe diabetic nephropathy, including more severe loss of kidney function. Tak et al [8] subsequently performed pharmacologic studies with STRING Network connecting NTN1 to ADORA2B Fig. 1 The adenosine A2b receptor, receptor for adenosine, and ADORA2B signals by G proteins, which activate adenylyl cyclase.…”