Klotho-deficient mice have accelerated aging phenotypes, whereas overexpression of Klotho in mice extends lifespan. Klotho is an anti-aging single-pass membrane protein predominantly produced in the kidney, with shedding of the amino-terminal extracellular domain into the systemic circulation. Circulating levels of soluble Klotho decrease with age, and the klotho gene is associated with increased risk of age-related diseases. The three forms of Klotho protein have distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors, functions as an obligatory co-receptor for FGF23, which is involved in aging and the development of chronic diseases via regulation of Pi and vitamin D metabolism. Secreted Klotho functions as a humoral factor with pleiotropic activities including regulation of oxidative stress, growth factor signaling, and ion homeostasis. Secreted Klotho is also involved in organ protection. The intracellular form of Klotho suppresses inflammation-mediated cellular senescence and mineral metabolism. Herein we provide a brief overview of the structure and function and recent research about Klotho.

Podocyte, the gatekeeper of the glomerular filtration barrier, is a primary target for growth factor and Ca2+ signaling whose perturbation leads to proteinuria. However, the effects of insulin action on store-operated Ca2+ entry (SOCE) in podocytes remain unknown. Here, we demonstrated that insulin stimulates SOCE by VAMP2-dependent Orai1 trafficking to the plasma membrane. Insulin-activated SOCE triggers actin remodeling and transepithelial albumin leakage via the Ca2+-calcineurin pathway in podocytes. Transgenic Orai1 overexpression in mice causes podocyte fusion and impaired glomerular filtration barrier. Conversely, podocyte-specific Orai1 deletion prevents insulin-stimulated SOCE, synaptopodin depletion, and proteinuria. Podocyte injury and albuminuria coincide with Orai1 upregulation at the hyperinsulinemic stage in diabetic (db/db) mice, which can be ameliorated by the suppression of Orai1-calcineurin signaling. Our results suggest that tightly balanced insulin action targeting podocyte Orai1 is critical for maintaining filter integrity, which provides novel perspectives on therapeutic strategies for proteinuric diseases, including diabetic nephropathy.

Wound healing is a physiological restorative response to tissue and cell injury. This process occurs in collaboration with a complex cascade of cellular events, including biochemical alterations to the extracellular matrix. Polydeoxyribonucleotide (PDRN) is a fragmented DNA mixture from Oncorhynchus mykiss or Oncorhynchus keta sperm known to promote tissue regeneration under different pathophysiological conditions. However, the most effective molecular size of PDRNs for promoting the wound healing process and quality has not been established. In the present study, the regeneration quality with low (<50 kDa), middle [classic PDRN; 50-1,500 kDa] and high (>1,500 kDa) molecular weight PDRNs in a skin wound healing mouse model was examined using hematoxylin and eosin, as well as Masson's trichrome stain. A 4 mm biopsy punch was used to produce wounds in the skin of the mice. PDRN-mediated cellular behavior and signaling were evaluated by in vitro scratch assay and western blot analysis, respectively. It was observed that the apparent surface wound healing processes were not significantly different between PDRN molecular sizes. Immunohistochemical analysis revealed that classic PDRN-injected mice exhibited less lipid accumulation with increased collagen composition. These results suggested that 50-1,500 kDa PDRN offers an effective DNA mixture to improve wound healing quality. Furthermore, classic PDRN increased cell migration via c-Jun N-terminal kinase signaling in human fibroblasts. The present study suggests an optimal PDRN molecular weight to promote wound healing, and novel approaches for therapeutic strategies to improve tissue regeneration quality.

No abstract

Klotho is a mammalian aging‐suppression gene and function as a suppressor of cancer. Here, we investigated the molecular mechanism of Klotho regulation of TRPC channels involving human breast cancer cell migration. Serum‐induced activation of TRPC and cell migration was specifically blocked by TRPC channel inhibitor, SKF96365, but not by voltage‐gated Ca2+ channel inhibitor, nimodipine. Treatment of purified Klotho protein inhibited TRPC6 channel activity. Interestingly, serum treatment increased the surface expression of TRPC6 channel. Klotho suppressed cell surface abundance of TRPC6 channels, whereas did not affect gating and activation kinetics of the channel. In addition, treatment of PI3K inhibitor (Wortmannin) or Erk1/2 inhibitor (U0126) blocked the serum‐induced augmentation of TRPC6. Suppression of vesicular trafficking by treatment of brefeldin A or tetanus toxin significantly decreased TRPC6 activity and Klotho regulation.Taken together, our data suggest that Klotho decreases surface expression of TRPC6 probably by reducing serum growth factor‐induced secretory pathway of the channel. Klotho may function as suppressor for human breast cancer cell migration caused by upregulation of TRPC6.[This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2010–0024789)]