In the renal proximal tubule, external Ca2+ ([Ca2+]o) is required for parathyroid hormone to elevate cytosolic Ca2+ ([Ca2+]i). However, other hormones increase [Ca2+]i in the absence of [Ca2+]o. These differences may arise from a diversity of signal transduction pathways acting on external and internal Ca2+ pools. However, Ca2+ influx may be necessary to expedite and maintain the rise of [Ca2+]i for a period after the initial surge. In this study, F- was used to probe the roles of intracellular Ca2+ mobilization, Ca2+ influx, and phosphoinositide (PI) hydrolysis on the surge of [Ca2+]i in rat proximal tubules. In the presence of external Ca2+; 1-20 mM F- evoked incremental rises of [Ca2+]i in tubules loaded with aequorin. Whereas 10 mM F- increased [Ca2+]i in the absence of [Ca2+]o, the time constant for the [Ca2+]i surge was increased. These findings are consistent with a role of Ca2+ influx on the effect of F- on [Ca2+]i. Indeed, 10 mM F- also enhanced the uptake of 45Ca2+, and promoted Ca2+ influx in aequorin- and fura-2-loaded, Ca(2+)-deprived tubules. In tubules, F- also activated PI hydrolysis with a time course that paralleled Ca2+ mobilization. The effect of F- on [Ca2+]i was not altered when the 39-kDa pertussis toxin substrate was inactivated with the toxin. This G protein was most likely Gi, because prostaglandin E2, an activator of Gi in tubules, dissociated the pertussis toxin-sensitive protein. The results support the notion that activation of a signal-transduction complex, the F- substrate, causes Ca2+ influx, mobilizes internal Ca2+, and activates PI hydrolysis in rat proximal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)
The removal of external Ca2+ ([Ca2+]o) reduces cytosolic Ca2+ ([Ca2+]i) in rat proximal tubules. In this report the role of external Na+ ([Na+]o) on the changes of [Ca2+]i and Ca2+ efflux caused by withdrawal of [Ca2+]o is described in rat renal proximal tubules. In aequorin-loaded tubules [Ca2+]i decreased from 235 +/- 25 to 48 +/- 16 (n = 4, P = 0.017), and 45Ca2+ fractional efflux ratio (45Ca2+ FER) increased from 0.94 +/- 0.03 to 1.64 +/- 0.19 (n = 6, P = 0.021) when Ca2+ was withdrawn from the bathing media of Krebs buffer (KB). The fall of [Ca2+]i, as well as the activation of 45Ca2+ FER, was reversed when [Na+]o in Ca(2+)-free KB was lowered isosmotically from 150 to 15 mM. However, when tubules were superfused with only 5 mM [Na+]o before [Ca2+]o was removed, [Ca2+]i also declined, but 45Ca2+ FER did not increase. The Na(+)-Ca2+ exchange inhibitor dichlorobenzamil (DCB) added after [Ca2+]o was removed evoked responses similar to [Na+]o removal, although DCB also inhibited internal Ca2+ release. These results are congruous with stimulation of Na+ influx in exchange for [Ca2+]i in Ca(2+)-free KB. However, even though total tubular Na+ was higher in Ca(2+)-free KB after 10 min, the initial rate of 22Na+ influx was not different without or with [Ca2+]o.(ABSTRACT TRUNCATED AT 250 WORDS)
Organismal aging is associated with typical aging phenotypes with structural changes and functional declines of organs. Hair loss is one of the most typical aging phenotypes in mammals, but the underlying mechanisms are still largely unclear. Here we report that the aging of hair follicles progresses in a step-wise manner with a distinct program in hair follicle stem cells (HFSCs) to cause irreversible hair loss. We found that DNA damage response (DDR) in murine HFSCs cause profound proteolysis of type XIIV collagen (COL17A1), a critical molecule for HFSC maintenance. Systematic fate analysis of those primed HFSCs with genetic stem cell tagging demonstrates that they locally initiate an epidermal differentiation program with the induction of c-MYC and NOTCH1, key regulators of epidermal differentiation within the stem cell niche, without renewing themselves or supplying follicular keratinocytes for hair growth. Those cells migrate from the bulge area through the junctional zone toward the epidermis and are eventually desquamated from the epidermal surface. Strikingly, similar aging processes were prematurely induced by Col17a1 deficiency in HFSCs or in progeric mouse models. In addition, we revealed that human scalps gradually cause hair follicle miniaturization by aging and COL17A1 expression is significantly impaired in miniaturized hair follicles through the provocation of COL17A1 protease by DDR. Furthermore, the entire aging program was significantly rescued by the forced maintenance of COL17A1 in HFSCs of aging mice, demonstrating that progression of such tissue aging programs can be controlled through changes in the expression of key molecule COL17A1 in mammalian somatic stem cells.
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