Phosphate Metabolism: From Physiology to Toxicity.

Systemic phosphate homeostasis is tightly controlled by the delicate cross-organ talk among intestine, kidney, bone, and parathyroid glands. The endocrine regulation of phosphate homeostasis is primarily mediated by fibroblast growth factor 23 (FGF23), vitamin D, and parathyroid hormone (PTH). Bone-derived FGF23 acts on the proximal tubular epithelial cells of the kidney to partly maintain the homeostatic balance of the phosphate. FGF23, through binding with its cell surface receptors in the presence of klotho, can activate downstream signaling kinases to reduce the functionality of the sodium-phosphate (NaPi) co-transporters of the kidney to influence the systemic phosphate homeostasis. Given the complexity of molecular regulation of phosphate homeostasis, providing information on all aspects of its homeostatic control in a single volume of a book is an overwhelming task. As the Editor, I have organized the chapters that I believe will provide necessary information on the physiologic regulation and pathologic dysregulation of phosphate in health and diseases. Readers will be able to use this volume as a quick reference for updated information on phosphate metabolism without prior acquaintance with the field.

Tacrolimus Decreases Cognitive Function by Impairing Hippocampal Synaptic Balance: a Possible Role of Klotho.

The influence of long-term tacrolimus treatment on cognitive function remains to be elucidated. Using a murine model of chronic tacrolimus neurotoxicity, we evaluated the effects of tacrolimus on cognitive function, synaptic balance, its regulating protein (Klotho), and oxidative stress in the hippocampus. Compared to vehicle-treated mice, tacrolimus-treated mice showed significantly decreased hippocampal-dependent spatial learning and memory function. Furthermore, tacrolimus caused synaptic imbalance, as demonstrated by decreased excitatory synapses and increased inhibitory synapses, and downregulated Klotho in a dose-dependent manner; the downregulation of Klotho was localized to excitatory hippocampal synapses. Moreover, tacrolimus increased oxidative stress and was associated with activation of the PI3K/AKT pathway in the hippocampus. These results indicate that tacrolimus impairs cognitive function via synaptic imbalance, and that these processes are associated with Klotho downregulation at synapses through tacrolimus-induced oxidative stress in the hippocampus.

Protective genes and pathways in Alzheimer's disease: moving towards precision interventions.

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that is characterized by neurodegeneration, cognitive impairment, and an eventual inability to perform daily tasks. The etiology of Alzheimer's is complex, with numerous environmental and genetic factors contributing to the disease. Late-onset AD is highly heritable (60 to 80%), and over 40 risk loci for AD have been identified via large genome-wide association studies, most of which are common variants with small effect sizes. Although these discoveries have provided novel insight on biological contributors to AD, disease-modifying treatments remain elusive. Recently, the concepts of resistance to pathology and resilience against the downstream consequences of pathology have been of particular interest in the Alzheimer's field as studies continue to identify individuals who evade the pathology of the disease even into late life and individuals who have all of the neuropathological features of AD but evade downstream neurodegeneration and cognitive impairment. It has been hypothesized that a shift in focus from Alzheimer's risk to resilience presents an opportunity to uncover novel biological mechanisms of AD and to identify promising therapeutic targets for the disease. This review will highlight a selection of genes and variants that have been reported to confer protection from AD within the literature and will also discuss evidence for the biological underpinnings behind their protective effect with a focus on genes involved in lipid metabolism, cellular trafficking, endosomal and lysosomal function, synaptic function, and inflammation. Finally, we offer some recommendations in areas where the field can rapidly advance towards precision interventions that leverage the ideas of protection and resilience for the development of novel therapeutic strategies.

Bovine serum albumin aggravates macrophage M1 activation and kidney injury in heterozygous Klotho-deficient mice via the gut microbiota-immune axis.

Klotho expression abnormalities induces kidney injury and chronic kidney disease, however, the underlying mechanism remains unclear. Here, Klotho+/- mice and wild-type mice were treated with low-dose bovine serum albumin (BSA). Pathological examination demonstrated that the area of glomerular collagen deposition and fibrosis in BSA-Kl-/+ mice was significantly larger than that in BSA-WT mice. The serum levels of superoxide dismutase, malondialdehyde, creatinine, and urea in BSA-Kl-/+ mice were significantly increased. Sequencing of gut microbiota 16S rRNA v3-v4 region indicated that BSA-Kl-/+ mice showed a significantly higher relative abundance of the genera Dubosiella, Akkermansia, Alloprevotella, and Lachnospiraceae and a significantly lower relative abundance of the genera Allobaculum and Muribaculaceae than BSA-WT mice. KEGG analysis revealed that the metabolic pathways of signal transduction, xenobiotic biodegradation and metabolism, and lipid metabolism increased significantly in BSA-Kl-/+ mice. Flow cytometry showed that the proportion of CD68+/CD11b+ cells in the peripheral blood was significantly higher in BSA-KL-/+ mice than that in BSA-WT mice. qPCR and western blot suggested that Klotho and Nrf2 expression in MΦ1 cells of BSA-KL-/+ mice was significantly decreased. Thus, the findings suggest during the immune activation and chronic inflammation induced by the gut microbiota imbalance in Klotho-deficient mice treated to BSA, disrupted expression of proteins in the Nrf2/NF-κB signaling pathway in monocyte-derived macrophage M1 cells leads to the aggravation of inflammation and kidney injury.