37 research outputs found
Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure
Pharmacological blockade of the N-and L-type calcium channel lessens renal injury in kidney disease patients. The significance of specific blockade of α1 subunit of N-type calcium channel, Ca[v]2.2, in diabetic nephropathy, however, remains to be clarified. To examine functional roles, we mated Ca[v]2.2-/- mice with db/db (diabetic) mice on the C57BLKS background. Ca[v]2.2 was localized in glomeruli including podocytes and in distal tubular cells. Diabetic Ca[v]2.2-/- mice significantly reduced urinary albumin excretion, glomerular hyperfiltration, blood glucose levels, histological deterioration and systolic blood pressure (SBP) with decreased urinary catecholamine compared to diabetic Ca[v]2.2+/+ mice. Interestingly, diabetic heterozygous Ca[v]2.2+/- mice also decreased albuminuria, although they exhibited comparable systolic blood pressure, sympathetic nerve activity and creatinine clearance to diabetic Ca[v]2.2+/+ mice. Consistently, diabetic mice with cilnidipine, an N-/L-type calcium channel blocker, showed a reduction in albuminuria and improvement of glomerular changes compared to diabetic mice with nitrendipine. In cultured podocytes, depolarization-dependent calcium responses were decreased by ω-conotoxin, a Ca[v]2.2-specific inhibitor. Furthermore, reduction of nephrin by transforming growth factor-β (TGF-β) in podocytes was abolished with ω-conotoxin, cilnidipine or mitogen-activated protein kinase kinase inhibitor. In conclusion, Ca[v]2.2 inhibition exerts renoprotective effects against the progression of diabetic nephropathy, partly by protecting podocytes
Spectral evolution of GRB 060904A observed with Swift and Suzaku -- Possibility of Inefficient Electron Acceleration
We observed an X-ray afterglow of GRB 060904A with the Swift and Suzaku
satellites. We found rapid spectral softening during both the prompt tail phase
and the decline phase of an X-ray flare in the BAT and XRT data. The observed
spectra were fit by power-law photon indices which rapidly changed from to within a few hundred
seconds in the prompt tail. This is one of the steepest X-ray spectra ever
observed, making it quite difficult to explain by simple electron acceleration
and synchrotron radiation. Then, we applied an alternative spectral fitting
using a broken power-law with exponential cutoff (BPEC) model. It is valid to
consider the situation that the cutoff energy is equivalent to the synchrotron
frequency of the maximum energy electrons in their energy distribution. Since
the spectral cutoff appears in the soft X-ray band, we conclude the electron
acceleration has been inefficient in the internal shocks of GRB 060904A. These
cutoff spectra suddenly disappeared at the transition time from the prompt tail
phase to the shallow decay one. After that, typical afterglow spectra with the
photon indices of 2.0 are continuously and preciously monitored by both XRT and
Suzaku/XIS up to 1 day since the burst trigger time. We could successfully
trace the temporal history of two characteristic break energies (peak energy
and cutoff energy) and they show the time dependence of while the following afterglow spectra are quite stable. This fact
indicates that the emitting material of prompt tail is due to completely
different dynamics from the shallow decay component. Therefore we conclude the
emission sites of two distinct phenomena obviously differ from each other.Comment: 19 pages, 9 figures, accepted for publication in PASJ (Suzaku 2nd
Special Issue
Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy
There is a hot debate concerning actual amount of albumin filtered through glomeruli and reabsorbed at proximal tubules in normal kidneys and diabetic conditions. To overcome current technical problems, we generated a drug-inducible megalin knockout mouse line, megalin(lox/lox);Ndrg1-CreER[T2] (or iMegKO), whose protein reabsorption can be shut off anytime by tamoxifen (Tam). After Tam administration, renal megalin protein expression was reduced by 92% compared to wild-type C57BL/6J mice, and renal reabsorption of intravenously-injected retinol binding protein was almost completely abrogated. Urinary albumin excretion increased to 175 μg/day (0.460 mg/mg-creatinine), suggesting that this was the amount of total nephron albumin filtration. Glomerular sieving coefficient of albumin was 1.7 x 10[-5]. By comparing streptozotocin-induced, Tam-treated, diabetic STZ;iMegKO mice with non-STZ;iMegKO mice, we estimated that daily albumin filtration was increased by 1.9-fold, reabsorption was increased by 1.8-fold, and reabsorption efficiency was reduced to 86% by development of diabetes (versus 96% in control). Such abnormalities were well normalized after insulin treatment. Another type 1 diabetic model of Akita;iMegKO mice showed equivalent results. This study reveals actual values and changes of albumin filtration and reabsorption in early diabetic nephropathy, bringing new insights into our understanding of renal albumin dynamics in hyperfiltration status of diabetic nephropath
HETE-2 Observations of the X-Ray Flash XRF 040916
A long X-ray flash was detected and localized by the instruments aboard the
High Energy Transient Explorer II (HETE-2) at 00:03:30 UT on 2004 September 16.
The position was reported to the GRB Coordinates Network (GCN) approximately 2
hours after the burst. This burst consists of two peaks separated by 200 s,
with durations of 110 s and 60 s. We have analyzed the energy spectra of the
1st and 2nd peaks observed with the Wide Field X-Ray Monitor (WXM) and the
French Gamma Telescope (FREGATE). We discuss the origin of the 2nd peak in
terms of flux variabilities and timescales. We find that it is most likely part
of the prompt emission, and is explained by the long-acting engine model. This
feature is similar to some bright X-ray flares detected in the early afterglow
phase of bursts observed by the Swift satellite.Comment: 9 pages, 4 figures, Accepted for publication in PAS