Tannic acid attenuates vascular calcification-induced proximal tubular cells damage through paracrine signaling

Vascular calcification is common in chronic kidney disease; however, the extent to which such condition can affect the renal microvasculature and the neighboring cell types is unclear. Our induced-calcification model in renal proximal tubular (PT) cells exhibited endoplasmic reticulum (ER) stress and oxidative damage, leading to apoptosis. Here, we utilized such calcification in mouse vascular smooth muscle (MOVAS-1) cells as a vascular calcification model, because it exhibited reactive oxygen species (ROS) generation, ER and oxidative stress, inflammatory, and apoptotic gene expressions. To demonstrate whether the vascular calcification condition can dictate the function of the adjacent PT cell layer, we utilized a Transwell multilayer culture system by combining those MOVAS-1 cells in the bottom chamber and polarized PT cells in the upper chamber to show the dimensional cross-signaling effect. Interestingly, calcification of MOVAS-1 cells, in this co-culture, induced H2O2 and lactate dehydrogenase (LDH) release leading to store-operated Ca2+ entry, ROS generation, and activation of oxidative, inflammatory, and apoptotic gene expressions in PT cells through paracrine signaling. Interestingly, application of tannic acid (TA) to either calcified MOVAS-1 or uncalcified PT cells diminished such detrimental pathway activation. Furthermore, the TA-mediated protection was much higher in the PT cells when applied on the calcified MOVAS-1 cells, and the delayed the pathological effects in neighboring PT cells can well be via paracrine signaling. Together, these results provide evidence of vascular calcification-induced PT cell damage, and the protective role of TA in preventing such pathological consequences, which can potentially be used as a nephroprotective remedy

Ablation of TRPC3 compromises bicarbonate and phosphate transporter activity in mice proximal tubular cells

Proximal tubular (PT) cells reabsorb most calcium (Ca ), phosphate (PO ), bicarbonate (HCO ), and oxalate (C O ) ions. We have shown that mice lacking Transient Receptor Potential Canonical 3 (TRPC3-/-) channel are moderately hypercalciuric with presentation of luminal calcium phosphate (CaP) crystals at the loop of Henle (LOH). However, other predisposing factors for such crystal deposition are unknown. Thus, we examined the distinctions in functional status of HCO , PO , and C O transporters in PT cells of wild type (WT) and TRPC3-/- mice by whole-cell patch clamp techniques to assess their contribution in the development of LOH CaP crystals. Here we show the development of concentration-dependent HCO -induced currents in all PT cells, which was confirmed by using specific HCO channel inhibitor, S0859. Interestingly, such activities were diminished in PT cells from TRPC3-/- mice, suggesting reduced HCO transport in absence of TRPC3. While PO -induced currents were also concentration-dependent in all PT cells (confirmed by PO channel inhibitor, PF-06869206), those activities were reduced in absence of TRPC3, suggesting lower PO reabsorption that can leave excess luminal PO . Next, we applied thiosulfate (O S ) as a competitive inhibitor of the SLC26a6 transporter upon C O current activation and observed a reduced C O -induced conductance which was greater in TRPC3-/- PT cells. Together, these results suggest that the reduced activities of HCO , PO , and C O transporters in moderately hypercalciuric (TRPC3-/-) PT cells can create a predisposing condition for CaP and CaP+CaOx tubular crystallization, enabling CaP crystal formation in LOH of TRPC3-/- mice

Store-operated Ca2+ signaling in dendritic cells occurs independently of STIM1

STIM2-dependent SOCE signaling pathway in DCs may regulate Ca2+ levels at the immunological synapse

Vascular Calcification and Stone Disease: A New Look towards the Mechanism

Calcium phosphate (CaP) crystals are formed in pathological calcification as well as during stone formation. Although there are several theories as to how these crystals can develop through the combined interactions of biochemical and biophysical factors, the exact mechanism of such mineralization is largely unknown. Based on the published scientific literature, we found that common factors can link the initial stages of stone formation and calcification in anatomically distal tissues and organs. For example, changes to the spatiotemporal conditions of the fluid flow in tubular structures may provide initial condition(s) for CaP crystal generation needed for stone formation. Additionally, recent evidence has provided a meaningful association between the active participation of proteins and transcription factors found in the bone forming (ossification) mechanism that are also involved in the early stages of kidney stone formation and arterial calcification. Our review will focus on three topics of discussion (physiological influences—calcium and phosphate concentration—and similarities to ossification, or bone formation) that may elucidate some commonality in the mechanisms of stone formation and calcification, and pave the way towards opening new avenues for further research

Novel Mutations in a Lethal Case of Lymphomatous Adult T Cell Lymphoma with Cryptic Myocardial Involvement

The autopsy of a 65-year-old diabetic African American male revealed significant left myocardial involvement by adult T-cell leukemia/lymphoma (ATLL) despite normal pre-mortem fluorodeoxyglucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT). Due to pre-existing diabetic cardiomyopathy with reduced ejection fraction (EF) and compatible imaging studies, cardiac lymphomatous involvement was not suspected. While peripheral blood was negative for leukemia, next-generation sequencing of a lymph node revealed at least eight novel mutations (AXIN1, R712Q, BARD1 R749K, CTNNB1 I315V, CUX1 P102T, DNMT3A S199R, FGFR2 S431L, LRP1B Y2560C and STAG2 I771M). These findings underscore a diagnostic pitfall in a rare lymphomatous variant of ATLL infiltrating myocardium and contribute to its molecular characterization