This series showcases video summaries of new findings published in the Journal of Clinical Investigation. This format allows authors to to provide a personally guided tour of their results and makes the research more accessible to a broad readership. The JCI accepts videos from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
The rare demyelinating disorder progressive multifocal leukoencephalopathy is triggered by JC virus infection of glial cells. Current models to study JC virus infection are limited to cell culture systems due to the human-selective nature of the virus. In this episode, Steve Goldman and colleagues develop a murine model that is permissive to JC virus infection. This study provides an important tool for future evaluation of JC virus pathogenesis and potential therapies.
Familial hyperkalemic hypertension (FHHt) is a rare monogenic disease that results from mutations in the kinases WNK1 and WNK4 or mutations in the ubiquitin ligase cullin 3 (CUL3) or the CUL3 substrate adaptor kelch-like 3 (KLHL3). Disease-associated mutations increase WNK kinase activity and thereby enhance activity of the Na-Cl transporter (NCC), which increases blood pressure and potassium levels. In this episode, David Ellison and colleagues reveal that FHHt-associated CUL3 mutant CUL3Δ403-459 exhibits enhanced ubiquitin ligase activity, leading to KLHL3 degradation and a subsequent increase in WNK kinase abundance. Moreover, kidney-specific deletion of Cul3 resulted in renal dysfunction, inflammation, and fibrosis in mice. This study provides insight in to the pathological mechanisms underlying FHHt-causing CUL3 mutations and demonstrates an essential role for CUL3 in the kidney.
The type 2 diabetes drug liraglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist that lowers blood glucose and reduces body weight. Liraglutide is being investigated for clinical use as a treatment for obesity; however, the mechanism of action underlying the associated weight loss is not clear. In this episode, Lotte Bjerre Knudsen and colleagues reveal that liraglutide mediates weight loss via neurons in the arcuate nucleus. GLP-1R signaling activated centrally projecting neurons that express proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART neurons), which regulate appetite and are activated by leptin and insulin. Liraglutide also inhibited neuropeptide Y-expressing neurons, which enhance appetite. The results of this study provide important insight into how liraglutide mediates weight loss.
Platelet accumulation and coagulation are key processes required to stop bleeding following blood vessel injury. Plasma fibronectin, which circulates freely in the blood, contains collagen, fibrin, and integrin binding sites and is well poised to contribute to hemostasis. In this episode, Heyu Ni and colleagues demonstrate that plasma fibronectin is not only vital to control bleeding in fibrin-deficient mice and in mice given anticoagulants, but may also inhibit thrombosis away from the site of injury. Together, the results from this study suggest that plasma fibronectin has therapeutic potential to control bleeding and modulate thrombosis.
There is a strong association between obesity and type 2 diabetes (T2D); however, the majority of obese individuals do not develop T2D, supporting that genetic predisposition is an important component of the disease. Alan Attie and colleagues previously revealed that polymorphisms in the Sorcs1 gene are associated with diabetes in obese mice. In this episode, Alan Attie, Angie Oler, and Melkam Kebede discuss their current study, which demonstrates that SORCS1 is required to replenish insulin secretory granules. Although obese Sorcs1-defient mice developed severe T2D, insulin secretion in response to a single glucose challenge did not appear dysfunctional in these animals. However, repeated challenge of islets isolated from Sorcs1-deficient mice resulted in loss of secretory granule production and insulin content. These results suggest that some insulin secretion defects in patients may not be revealed by a single secretagogue challenge.
Copyright © 2014 American Society for Clinical Investigation