Our meta-analysis suggests evidence for cigarette smoking as an independent risk factor for incident CKD. Future studies are required to investigate whether smoking cessation can decrease incident CKD in the general adult population.
We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy prevents volume-overload hypertrophy in dogs with chronic mitral regurgitation (MR). Seven adult mongrel dogs receiving ramipril (R; 10 mg orally, twice/day) for 4 mo were compared with 11 dogs receiving no R (N) for 4 mo after induction of MR. Cine-magnetic resonance imaging demonstrated that left ventricular (LV) mass increased in the R-MR dogs [80 +/- 4 (SE) to 108 +/- 7 g, P < 0.01] and in the N-MR dogs (92 +/- 7 to 112 +/- 8 g, P < 0.001). LV myocyte cell length was greater in the R-MR and N-MR dogs (203 +/- 6 and 177 +/- 10 microns, respectively) than in normal (144 +/- 4 microns, P < 0.05) dogs. There was significant loss of the collagen weave pattern by scanning electron microscopy in both R-MR and N-MR dogs. LV ACE and chymase activities were significantly elevated in R-MR and N-MR compared with normal dogs. LV angiotensin II (ANG II) levels in the R-MR dogs (28 +/- 12 pg/g) were reduced to levels seen in normal dogs (28 +/- 4 pg/g) compared with N-MR dogs (72 +/- 11 pg/g, P < 0.05). Steady-state AT1-receptor mRNA levels decreased 66% in N-MR compared with normal dogs (P < 0.001) and increased 1.5-fold in R-MR compared with normal dogs (P < 0.01). Thus upregulation of the AT1 receptor in the R-MR hearts may provide a mechanism by which normal intracardiac ANG II levels could continue to mediate LV hypertrophy. However, the mechanism of dissolution collagen weave in both N-MR and R-MR hearts may be related to the stretch of volume overload.
SummaryThe Nur77/Nurrl family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)-mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced. The transgene consisted of a truncated Nur77 (ANur77) gene encoding the DNA-binding domain of Nur77 ligated to a TCR-[3 enhancer resulting in early expression in thymocytes. Apoptosis of CD4+CD8 + thymocytes mediated by CD3/TCR signaling was greatly inhibited in the ANur77 Tg mice, compared with non-Tg littermates, after treatment with anti-CD3 or anti-TCR antibody in vivo and in vitro. Clonal deletion of self-reactive T cells was investigated in ANur77-Db/HY TCR-ot/~3 double Tg mice. There was a five-fold increase in the total number of thymocytes expressing self-reactive Db/HY TCR-et/~3 in the ANur77-TCR-ot/[3 double Tg male mice. Deficient clonal deletion of self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8 + thymocytes that expressed Tg TCR-a/[~. There was an eight-fold increase in CD8 +, DB/Hy TCR-ot/[3 T cells in the lymph nodes (LN) of ANur77-Db/Hy TCR-o_/[3 double Tg compared with Db/Hy TCR-0~/I3 Tg male mice. In spite of defective clonal deletion, the T cells expressing the Tg TCR were functionally anergic. In vivo analysis revealed increased activation and apoptosis of T cells associated with increased expression of Fas and Fas ligand in LN of ANur77-Db/Hy TCR-oJI3 double Tg male mice. These results indicate that inhibition of Nur77/Nurrl DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen.
Native amiloride-sensitive Na ؉ channels exhibit a variety of biophysical properties, including variable sensitivities to amiloride, different ion selectivities, and diverse unitary conductances. The molecular basis of these differences has not been elucidated. We tested the hypothesis that co-expression of ␦-epithelial sodium channel (ENaC) underlies, at least in part, the multiplicity of amiloride-sensitive Na ؉ conductances in epithelial cells. For example, the ␦-subunit may form multimeric channels with ␣␥-ENaC. Reverse transcription-PCR revealed that ␦-ENaC is co-expressed with ␣␥-subunits in cultured human lung (H441 and A549), pancreatic (CFPAC), and colonic epithelial cells (Caco-2). Indirect immunofluorescence microscopy revealed that ␦-ENaC is co-expressed with ␣-, -, and ␥-ENaC in H441 cells at the protein level. Measurement of current-voltage relationships revealed that the cation selectivity ratios for Na ؉ /Li ؉ /K ؉ /Cs ؉ /Ca 2؉ /Mg 2؉ , the apparent dissociation constant (K i ) for amiloride, and unitary conductances for ␦␣␥-ENaC differed from those of both ␣␥-and ␦␥-ENaC (n ؍ 6). The contribution of the ␦ subunit to P Li /P Na ratio and unitary Na ؉ conductance under bi-ionic conditions depended on the injected cRNA concentration. In addition, the EC 50 for proton activation, mean open and closed times, and the self-inhibition time of ␦␣␥-ENaC differed from those of ␣␥-and ␦␥-ENaC. Co-immunoprecipitation of ␦-ENaC with ␣-and ␥-subunits in H441 and transfected COS-7 cells suggests an interaction among these proteins. We, therefore, concluded that the interactions of ␦-ENaC with other subunits could account for heterogeneity of native epithelial channels.
Programmed cell death represents an important pathogenic mechanism in various autoimmune diseases. Type I diabetes mellitus (IDDM) is a T cell-dependent autoimmune disease resulting in selective destruction of the β cells of the islets of Langerhans. β cell apoptosis has been associated with IDDM onset in both animal models and newly diagnosed diabetic patients. Several apoptotic pathways have been implicated in β cell destruction, including Fas, perforin, and TNF-α. Evidence for Fas-mediated lysis of β cells in the pathogenesis of IDDM in nonobese diabetic (NOD) mice includes: 1) Fas-deficient NOD mice bearing the lpr mutation (NOD-lpr/lpr) fail to develop IDDM; 2) transgenic expression of Fas ligand (FasL) on β cells in NOD mice may result in accelerated IDDM; and 3) irradiated NOD-lpr/lpr mice are resistant to adoptive transfer of diabetes by cells from NOD mice. However, the interpretation of these results is complicated by the abnormal immune phenotype of NOD-lpr/lpr mice. Here we present novel evidence for the role of Fas/FasL interactions in the progression of NOD diabetes using two newly derived mouse strains. We show that NOD mice heterozygous for the FasL mutation gld, which have reduced functional FasL expression on T cells but no lymphadenopathy, fail to develop IDDM. Further, we show that NOD-lpr/lpr mice bearing the scid mutation (NOD-lpr/lpr-scid/scid), which eliminates the enhanced FasL-mediated lytic activity induced by Fas deficiency, still have delayed onset and reduced incidence of IDDM after adoptive transfer of diabetogenic NOD spleen cells. These results provide evidence that Fas/FasL-mediated programmed cell death plays a significant role in the pathogenesis of autoimmune diabetes.
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