The Body-wide Transcriptome Landscape of Disease Models.

Virtually all diseases affect multiple organs. However, our knowledge of the body-wide effects remains limited. Here, we report the body-wide transcriptome landscape across 13-23 organs of mouse models of myocardial infarction, diabetes, kidney diseases, cancer, and pre-mature aging. Using such datasets, we find (1) differential gene expression in diverse organs across all models; (2) skin as a disease-sensor organ represented by disease-specific activities of putative gene-expression network; (3) a bone-skin cross talk mediated by a bone-derived hormone, FGF23, in response to dysregulated phosphate homeostasis, a known risk-factor for kidney diseases; (4) candidates for the signature activities of many more putative inter-organ cross talk for diseases; and (5) a cross-species map illustrating organ-to-organ and model-to-disease relationships between human and mouse. These findings demonstrate the usefulness and the potential of such body-wide datasets encompassing mouse models of diverse disease types as a resource in biological and medical sciences. Furthermore, the findings described herein could be exploited for designing disease diagnosis and treatment.

Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation.

BACKGROUND: An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum (ER) stress. As a defense mechanism, cells express ER stress inducible chaperons, such as oxygen-regulated proteins 150 (ORP150) and glucose-regulated proteins (GRPs). While ER stress is important in various diseases, a pathophysiologic role for ER stress in kidney disease remains elusive. Here we investigate expression of ER stress proteins in cultured rat podocytes as well as in our recently developed animal model of abnormal protein retention within the ER of podocytes (i.e., megsin transgenic rat). METHODS: The expression of ER stress inducible proteins (ORP150, GRP78, or GRP94) in cultured podocytes treated with tunicamycin, A23187, SNAP, hypoxia, or hyperglycemia, and the renal tissues or isolated glomeruli from megsin transgenic rats was analyzed by Western blotting analysis, immunohistochemistry, or confocal microscopy. RESULTS: Cultured podocytes demonstrated that treatment with tunicamycin, A23187, and SNAP, but not hypoxia or hyperglycemia, up-regulate expression of ER stress proteins. Extracts of isolated glomeruli from megsin transgenic rats reveal marked up-regulation of ER stress chaperones in podocytes, which was supported by immunohistochemical analysis. Confocal microscopy revealed that ER stress in podocytes was associated with cellular injury. Podocytes of transgenic rats overexpressing a mutant megsin, without the capacity for polymerization within the ER, do not exhibit ER stress or podocyte damage, suggesting a pathogenic role of ER retention of polymerized megsin. CONCLUSION: This paper implicates a crucial role for the accumulation of excessive proteins in the podocyte ER in the induction of ER stress and associated podocyte injury.

Novel serpinopathy in rat kidney and pancreas induced by overexpression of megsin.

The intracellular polymerization of abnormal serine protease inhibitors (serpins) results in liver or neuronal cell abnormalities recently identified as "serpinopathies." It was demonstrated in transgenic rats that overexpression of megsin, a recently discovered serpin located in the kidney, produces renal and pancreatic lesions characteristic of serpinopathies. Megsin expression is elevated in a variety of organs, including kidney and pancreas. Periodic acid-Schiff-positive, diastase-resistant intracellular inclusions develop only in the kidney and the pancreas. They correspond to electron-dense deposits, shown to contain megsin by immunohistochemistry and immunoelectron microscopy. In the kidney, inclusions are located mainly in the endoplasmic reticulum of glomerular epithelial, distal, and collecting duct cells, and are associated with massive proteinuria and an impaired renal function. In the pancreas, similar inclusions are found in the exocrine and Langerhans islet cells, where islet beta cells are reduced as a result of apoptosis. They are associated with diabetes with low insulin levels. The animals have an impaired growth and die within 10 wk. Rats that overexpress a mutant megsin, characterized by a deficient conformational transition activity, do not develop the serpinopathy, suggesting that some conformational flexibility of the serpin is required for the development of serpinopathy. This model of serpinopathy is the first to involve the kidney and the pancreas.