Regulation of renin gene expression in kidneys of eNOS- and nNOS-deficient mice

Our study aimed to assess the roles of nitric oxide derived from endothelium NO-synthase (eNOS) and macula densa neuronal NO-synthase (nNOS) in the regulation of renal renin expression. For this purpose renin mRNA levels and renin content were determined in kidneys of wild-type (wt), nNOS-deficient (nNOS-/-), and eNOS-deficient (eNOS-/-) mice, in which the renin system was suppressed by feeding a high-salt diet (NaCl 4%), or was stimulated by feeding a low-salt (NaCl 0.02%) diet together with the converting-enzyme inhibitor ramipril (10 mg kg(-1) day(-1)). In all mouse strains, renin mRNA levels were inversely related to the rate of sodium intake. In eNOS-/- mice renin mRNA levels and renal renin content were 50% lower than in wt mice at each level of salt intake, whilst in nNOS-/- mice renin expression was not different from wt controls. Administration of the general NO-synthase inhibitor nitro-L-arginine methyl ester (L-NAME, 50 mg kg(-1) day(-1)) to mice kept on the low-salt/ramipril regimen caused a decrease of renal renin mRNA levels in wt and nNOS-/- mice, but not in eNOS-/- mice. These observations suggest that neither eNOS nor nNOS is essential for up- or downregulation of renin expression. eNOS-derived NO appears to enhance renin expression, whereas nNOS-derived NO does not.     

Tolerance in mixed chimerism – a role for regulatory cells?

The establishment of mixed hematopoietic chimerism induces life-long donor-specific organ graft tolerance while obviating the need for chronic immunosuppression. Recent advances have dramatically reduced the conditioning toxicity required to achieve mixed chimerism. We argue that the achievement of high levels of donor chimerism ensures life-long deletion of donor-reactive T cells, precluding and obviating the need for regulatory mechanisms in the maintenance of tolerance. However, in situations where high levels of donor chimerism cannot be established or sustained, control of immune responsiveness can be achieved through additional mechanisms, including regulatory T cells.     

Surface morphology and wear mechanisms of four clinically relevant biomaterials after hip simulator testing

The surfaces of worn components hold clues to the underlying wear mechanisms. Previous evidence suggested that the absolute wear rates of acetabular components in a hip simulator were related to mechanical behavior; we hypothesized that the surface morphology of the liners might also be sensitive to mechanical properties. A noncontact, three-dimensional surface topography measurement system based on white light interferometry was used to quantify the surface morphology of ultra-high molecular weight polyethylene, polytetrafluoroethylene, high-density polyethylene, and polyacetal liners, and their corresponding femoral heads, after 3 million cycles in a multi-directional hip simulator. Comparisons were made with the fatigue soaked and control (as machined) components. Statistically significant power law relationships were observed between the arithmetic mean surface roughness (R(a)) of the worn acetabular liners and the volumetric wear rate in the hip simulator (p < 0.01, r(2) = 0.52). Significant relationships were also observed between R(a) and the elastic and large deformation mechanical behavior of the liner materials, measured directly from the wear-tested liners using the small punch test (p < 0.01, r(2) = 0.54-0.81). The results support the hypothesis that wear mechanisms of acetabular liners during hip simulator testing are related to surface morphology in conjunction with the mechanical behavior of the polymeric materials.     

Amiloride enhances the secretion but not the synthesis of renin in renal juxtaglomerular cells

In this study we have examined a potential role of the sodium/proton exchange system in the regulation of renin secretion. We found that the inhibitors of the Na⁺/H⁺ antiport, amiloride (1 mM) and ethylisopro-pylamiloride (EIPA, 50 M), led to a 125% increase of renin secretion from cultured mouse juxtaglomerular cells. The stimulatory effect of EIPA on renin secretion was dependent on the extracellular concentrations of sodium and hydrogen ions. While lowering the extracellular pH from 7.3 to 7.0, and lowering [Na⁺]_e from 130 mM to 5 mM had no effect on basal renin release, it markedly attenuated or even blunted the effect of EIPA on renin secretion. The stimulatory effect of forskolin on renin secretion, however, was not altered by decreases of extracellular pH and of sodium. Inhibition of basal renin release was achieved with angiotensin II (1 M). In the presence of EIPA the inhibitory effect angiotensin II was markedly attenuated. Although effective on renin secretion, neither amiloride nor EIPA exerted a significant effect on the de novo synthesis of renin in cultured mouse JG cells. These findings are compatible with the idea that an amiloride-sensitive transport process, presumably the Na⁺/H⁺ exchanger, acts indirectly as an inhibitory signal transduction system for renin secretion from renal juxtaglomerular cells.     

Calcitonin gene products and the kidney

Summary Calcitonin gene-related peptide (CGRP) is localized in capsaicin-sensitive nerve fibres in the kidney and urogenital tract whereas calcitonin reaches the kidney through the general circulation. Systemic infusion of CGRP and perfusion of isolated rat kidney reduces vascular resistance, and increases renal blood flow and glomerular filtration. CGRP stimulates renin secretion in vivo and in vitro and inhibits contraction of isolated rat mesangial cells by angiotensin II. Calcitonin does not affect vascular resistance, renal blood flow and glomerular filtration, and is less potent in stimulating renin secretion, and does not alter contraction of isolated rat mesangial cells by angiotensin II. CGRP also exerts renal tubular effects brought about probably through interaction with calcitonin receptors. To this end, increased excretion of sodium and chloride, and stimulation of urinary flow are less pronounced with CGRP than with calcitonin. Calcitonin, moreover, stimulates the fractional urinary excretion of calcium and phosphate.     

Bilateral simultaneous tubal sextuplets: pregnancy after in-vitro fertilization--embryo transfer following salpingectomy

The presence of a damaged tube has been suggested in recent studies to have a negative effect on in-vitro fertilization (IVF) outcome. Performing bilateral salpingectomy prior to IVF to maximize pregnancy rates may also result in unnecessary surgery. This case is also an example of the occurrence of interstitial pregnancy after salpingectomy. This unusual type of ectopic pregnancy must be kept in mind when evaluating a patient suspected of a possible early abnormal gestation after assisted reproductive technolologies.      

The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell- mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ- specific autoimmune disease.