GDNF/Ret signaling and renal branching morphogenesis: From mesenchymal signals to epithelial cell behaviors

Signaling by GDNF through the Ret receptor tyrosine kinase is required for the normal growth and morphogenesis of the ureteric bud (UB) during kidney development. Recent studies have sought to understand the precise role of Ret signaling in this process, and the specific responses of UB cells to GDNF. Surprisingly, the requirement for Gdnf and Ret was largely relieved by removing the negative regulator Spry1, revealing unexpected functional overlap between GDNF and FGF10. However, the kidneys that developed without Gdnf/Ret and Spry1 displayed significant branching abnormalities, suggesting a unique role for GDNF in fine-tuning UB branching. GDNF/Ret signaling alters patterns of gene expression in UB tip cells, and one critical event is upregulation of the ETS transcription factors Etv4 and Etv5. Mice lacking Etv4 and Etv5 fail to develop kidneys. Thus, these genes represent key components of a regulatory network downstream of Ret. Studies of chimeric embryos in which a subset of cells lack either Ret, Etv4/5 or Spry1 have revealed an important role for this pathway in cell movement. Ret signaling, via Etv4 and Etv5, promotes competitive cell rearrangements in the nephric duct, in which the cells with the highest level of Ret signaling preferentially migrate to form the first ureteric bud tip

Birth weight, malnutrition and kidney-associated outcomes--a global concern

An adverse intrauterine environment is associated with an increased risk of elevated blood pressure and kidney disease in later life. Many studies have focused on low birth weight, prematurity and growth restriction as surrogate markers of an adverse intrauterine environment; however, high birth weight, exposure to maternal diabetes and rapid growth during early childhood are also emerging as developmental risk factors for chronic diseases. Altered programming of nephron number is an important link between exposure to developmental stressors and subsequent risk of hypertension and kidney disease. Maternal, fetal, and childhood nutrition are crucial contributors to these programming effects. Resource-poor countries experience the sequential burdens of fetal and childhood undernutrition and subsequent overnutrition, which synergistically act to augment the effects of developmental programming; this observation might explain in part the disproportionate burden of chronic disease in these regions. Numerous nutritional interventions have been effective in reducing the short-term risk of low birth weight and prematurity. Understanding the potential long-term benefits of such interventions is crucial to inform policy decisions to interrupt the developmental programming cycle and stem the growing epidemics of hypertension and kidney disease worldwide

Intracranial Pressure and Multimodal Monitoring

Secondary brain injury results from ischemia, tissue hypoxia, and a cascade of ongoing metabolic events. Neuromonitoring has evolved over the last two decades with the goal of preventing, detecting, and attenuating the damage from these secondary events. Typical monitored parameters include intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Advanced multimodal monitoring includes monitoring of cerebral blood flow (CBF), brain tissue oxygenation (transcranial oximetry, jugular bulb oximetry, brain tissue oxygen tension), and brain metabolism (intracerebral microdialysis). In this chapter, we will review basic principles of brain physiology and the complex and dynamic interactions between these parameters. In the future, neuromonitoring will be supported by advanced signal processing and analysis that will enable clinicians to synthesize information and form hypotheses that best explain the current situation. Such an integrated system will translate data into actionable information and provide situational awareness