Swerving away from diabetic nephropathy by means of divine guidance

Abstract

The netrins are a class of proteins involved in axon guidance. They are genetically conserved across nematodes, flies, amphibians, and mammals. Structurally, the netrins resemble the basement membrane protein, laminin. The netrins are chemotropic. Netrin attraction is mediated through "deleted in colorectal carcinoma" (cUNC-40/DCC) cell surface receptors, while repulsion requires UNC-5 receptors. Netrin-1 is found in many sites of the central nervous system as well as in the somatic mesoderm, pancreas, and cardiac muscle. More recent research has linked netrin to the development and formation of non-neural tissue, the detection of cancer, and other diseases. Even myocardial infarction, Alzheimer's disease, and kidney diseases have been found to involve netrins, particularly netrin-1 [1]. As a matter of fact, the kidney has one of the highest netrin-1 expressions. With ischemia/reperfusion, netrin-1 protein expression in renal tubular cells increases further and urinary netrin-1 excretion increases accordingly [2]. Netrin-1's appearance in the urine suggested that netrin-1 might serve as an acute kidney injury "biomarker." A survey of 13 patients with acute kidney injury supported that point of view [3].What is netrin-1 doing in the kidney? Further work by the same group initially exploring the role of netrin-1 in the kidney showed that netrin-1 increased renal tubular epithelial cell proliferation and migration through the UNC5B receptor. Moreover, the increase in cell proliferation, but not migration, was mediated via activation of Akt and ERK pathways [4]. How does netrin-1 work? To address that issue, Wang et al. studied a transgenic model overexpressing netrin-1 in the kidney [5]. Acute ischemia/reperfusion was the model they employed. Netrin-1 overexpression exerted a protective effect from acute kidney injury. Mechanisms included preservation of morphology, reduced cytokine expression, and reduced oxidative stress in the kidney of transgenic mice, compared to wild-type mice. The authors concluded that netrin-1 protects renal tubular epithelial cells against ischemia reperfusioninduced injury by increasing proliferation of recovering cells and suppressing apoptosis in injured cells. However, mechanistically, these studies were insufficient.Since the ischemic kidney is particularly prone to reperfusion-elicited inflammation, the group next sought to determine the function of netrin-1 and its receptor UNC5B in renal ischemia-reperfusion-induced inflammation [6]. They reasoned that ischemia/reperfusion injury rests on inflammatory processes. Renal ischemia-reperfusion caused a rapid decrease in serum netrin-1 levels. However, the administration of recombinant netrin-1, before or after renal ischemia-reperfusion, reduced kidney injury, resulted in apoptosis, and lowered monocyte and neutrophil infiltration. Furthermore, the cytokines IL-6, IL-1β, and TNF-α and the chemokines MCP-1, macrophage-derived cytokine, monokine-induced IFN-γ, keratinocyte-derived chemokine, and chemokine with-6-cysteines production were...