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Biomedical subjects

Leon G Fine

Publications and source records attributed to Leon G Fine.

12 recordsLinked to original sources
PubMed2006

Intrarenal oxygenation in chronic renal failure.

In chronic renal failure (CRF), renal impairment correlates with tubulointerstitial fibrosis characterized by inflammation, interstitial expansion with accumulation of extracellular matrix (ECM), tubular atrophy and vascular obliteration. Tubulointerstitial injury subsequent to glomerular sclerosis may be induced by proteinuria, leakage of glomerular filtrate or injury to the post-glomerular peritubular capillaries (hypoxia). In vivo data in animal models suggest that CRF is associated with hypoxia, with the decline in renal Po2 preceding ECM accumulation. Chronic renal failure is characterized by loss of microvascular profiles but, in the absence of microvascular obliteration, hypoxia can occur by a variety of complementary mechanisms, including anaemia, decreased capillary flow, increased vasoconstriction, increased metabolic demand and increased diffusion distances due to ECM deposition. Hypoxia regulates a wide array of genes, including many fibrogenic factors. Hypoxia-inducible factors (HIF) are the major, but not the sole, transcriptional regulators in the hypoxic response. In CRF, hypoxia may play a role in the sustained inflammatory response. In vitro studies in tubulointerstitial cells suggest that hypoxia can induce profibrogenic changes in proximal tubular epithelial cells and interstitial fibroblasts consistent with changes observed in CRF in vivo. The effect of hypoxia on renal microvascular cells warrants investigation. Hypoxia may play a role in the recruitment, retention and differentiation of circulating progenitor cells to the kidney contributing to the disease process and may also affect intrinsic stem cell populations. Chronic hypoxia in CRF fails to induce a sustained angiogenic response. Therapeutic manipulation of the hypoxic response may be of benefit in slowing progression of CRF. Potential therapies include correction of anaemia, inhibition of the renin-angiotensin system, administration of exogenous pro-angiogenic factors to protect the microvasculature, activation of HIF and hypoxia-mediated targeting of engineered progenitor cells.

Animals↗
PubMed2005

Proteomics profiling of nuclear proteins for kidney fibroblasts suggests hypoxia, meiosis, and cancer may meet in the nucleus.

Proteomics methods were used to characterize proteins that change their form or abundance in the nucleus of NRK49F rat kidney fibroblasts during prolonged hypoxia (1% O(2), 12 h). Of the 791 proteins that were monitored, about 20% showed detectable changes. The 51 most abundant proteins were identified by mass spectrometry. Changes in nuclear receptor transcription factors (THRalpha1, RORalpha4, HNF4alpha, NUR77), other transcription factors (GATA1, AP-2alpha, OCT1, ATF6alpha, ZFP161, ZNF354A, PDCD2), and transcription cofactors (PC4, PCAF, MTA1, TCEA1, JMY) are indicative of major, co-ordinated changes in transcription. Proteins involved in DNA repair/recombination, ribosomal RNA synthesis, RNA processing, nuclear transport, nuclear organization, protein translation, glycolysis, lipid metabolism, several protein kinases (PKCdelta, MAP3K4, GRK3), as well as proteins with no established functional role were also observed. The observed proteins suggest nuclear regulatory roles for proteins involved in cytosolic processes such as glycolysis and fatty acid metabolism, and roles in overall nuclear structure/organization for proteins previously associated with meiosis and/or spermatogenesis (synaptonemal complex proteins 1 and 2 (SYCP1, SYCP2), meiosis-specific nuclear structural protein 1 (MNS1), LMNC2, zinc finger protein 99 (ZFP99)). Proteins associated with cytoplasmic membrane functions (ACTN4, hyaluronan mediated motility receptor (RHAMM), VLDLR, GRK3) and/or endocytosis (DNM2) were also seen. For 30% of the identified proteins, new isoforms indicative of alternative transcription were detected (e.g., GATA1, ATF6alpha, MTA1, MLH1, MYO1C, UBF, SYCP2, EIF3S10, MAP3K4, ZFP99). Comparison with proteins involved in cell death, cancer, and testis/meiosis/spermatogenesis suggests commonalities, which may reflect fundamental mechanisms for down-regulation of cellular function.

Animals↗
PubMed2004

Cellular defense against H2O2-induced apoptosis via MAP kinase-MKP-1 pathway.

Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is an oxidative stress-inducible gene. In this study, we investigated signaling pathways involved in oxidative stress-induced MKP-1 expression and its role in apoptosis of rat mesangial cells. Northern and Western blot analyses showed that H(2)O(2) induced expression of MKP-1 mRNA and protein in a dose-dependent manner, without affecting the stability of the transcript. H(2)O(2) induced phosphorylation of extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun N-terminal kinase and consequently activated activator protein 1 (AP-1). Selective inhibitors of individual MAP kinases or a dominant-negative mutant of c-jun significantly suppressed the expression of MKP-1 by H(2)O(2). Inhibition of MKP-1 by a protein tyrosine phosphatase inhibitor (vanadate) enhanced H(2)O(2)-triggered apoptosis. Consistently, transfection with a wild-type MKP-1, but not its catalytically inactive mutant MKP-1CS, attenuated H(2)O(2)-induced apoptosis. These data elucidate, for the first time, that induction of MKP-1 by H(2)O(2) is mediated by the MAP kinase-AP-1 pathway and that the induced MKP-1 is involved in cellular defense against oxidative stress-induced apoptosis of mesangial cells.

Animals↗
PubMed2004

Retinoids in nephrology: promises and pitfalls.

BACKGROUND: Retinoids, a family of vitamin A metabolites or analogs, play an important role in regulating cell proliferation, differentiation, and apoptosis. METHODS: The biological importance of retinoids in the kidney and the potential of retinoids in the treatment of renal diseases are reviewed. RESULTS: Vitamin A deficiency and mutations of retinoid nuclear receptors cause abnormalities in fetal kidneys, which might predispose to adult diseases such as hypertension. Further, the therapeutic value of retinoids in animal models of kidney diseases, such as lupus nephritis, puromycin aminonucleoside nephrosis, anti-glomerular basement membrane nephritis, mesangioproliferative nephritis, and acute renal allograft rejection has been unveiled recently. Retinoids target mesangial cells, podocytes, tubular epithelial cells, interstitial fibroblasts, as well as lymphocytes and macrophages. The anti-inflammation, anti-coagulation effects, and the proliferation- and immunity-modulating actions of retinoids, have been widely appreciated. Our recent in vitro data revealed a direct antifibrotic effect and a cytoprotective effect of retinoids in various renal cell types. In animal studies, the adverse effects of retinoids are generally minimal; however, the clinical use of retinoids in other diseases points to some major side effects. In addition, in vitro, retinoids can induce lipid accumulation in smooth muscle cells and macrophages and increase expression of some proinflammatory molecules, indicating that their clinical toxicity profile in the setting of renal diseases needs to be better understood. CONCLUSION: Retinoids not only are important in renal development, but also show promise as a new generation of renal medication and deserve to be tested in clinical trials to clarify their full potential.

Animals↗
PubMed2003

How to evaluate and improve the quality and credibility of an outcomes database: validation and feedback study on the UK Cardiac Surgery Experience.

OBJECTIVES: To assess the quality and completeness of a database of clinical outcomes after cardiac surgery and to determine whether a process of validation, monitoring, and feedback could improve the quality of the database. DESIGN: Stratified sampling of retrospective data followed by prospective re-sampling of database after intervention of monitoring, validation, and feedback. SETTING: Ten tertiary care cardiac surgery centres in the United Kingdom. INTERVENTION: Validation of data derived from a stratified sample of case notes (recording of deaths cross checked with mortuary records), monitoring of completeness and accuracy of data entry, feedback to local data managers and lead surgeons. MAIN OUTCOME MEASURES: Average percentage missing data, average kappa coefficient, and reliability score by centre for 17 variables required for assignment of risk scores. Actual minus risk adjusted mortality in each centre. RESULTS: The database was incomplete, with a mean (SE) of 24.96% (0.09%) of essential data elements missing, whereas only 1.18% (0.06%) were missing in the patient records (P<0.0001). Intervention was associated with (a) significantly less missing data (9.33% (0.08%) P<0.0001); (b) marginal improvement in reliability of data and mean (SE) overall centre reliability score (0.53 (0.15) v 0.44 (0.17)); and (c) improved accuracy of assigned Parsonnet risk scores (kappa 0.84 v 0.70). Mortality scores (actual minus risk adjusted mortality) for all participating centres fell within two standard deviations of the mean score. CONCLUSION: A short period of independent validation, monitoring, and feedback improved the quality of an outcomes database and improved the process of risk adjustment, but with substantial room for further improvement. Wider application of this approach should increase the credibility of similar databases before their public release.

Cardiac Surgical Procedures↗
PubMed2003

Angiotensin II blockade augments renal cortical microvascular pO2 indicating a novel, potentially renoprotective action.

BACKGROUND: The existence of tubulointerstitial damage in most cases of progressive human glomerular disease suggests that this compartment of the kidney is likely to be targeted by renoprotective agents which slow the progression of disease. Angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of renal protection. Since we have proposed that perturbation of the interstitial capillary circulation with consequent chronic hypoxia could be critical to the progressive nature of many renal diseases, we developed a dynamic method of measuring renal cortical pO(2) and sought to determine whether agents which block the renal effects of angiotensin II (AII) could affect interstitial microvascular oxygenation in the normal rat kidney. METHODS: Instrumented, anaesthetised adult male Sprague-Dawley rats were studied. Cortical microvascular pO(2 )was measured on the surface of the exposed kidney using protoporphyrin phosphorescence. Blood pressure and renal artery blood flow (Doppler flowmetry) were measured concurrently over a 180-min experimental period. Animals received non-hypotensive doses of enalaprilat (100 microg/kg i.v.) or candesartan (40 microg/kg i.v.) either at the beginning of the experimental period or after an initial decline in cortical microvascular pO(2). RESULTS: After a 30-min stabilisation period there was a slow decline in pO(2 )from 48.6 +/- 4.1 to 38.5 +/- 6.9 mm Hg in control animals over the 180-min experimental period. Administration of the ACE inhibitor, enalaprilat at the beginning of the experimental period, completely abrogated this decline and protected pO(2) levels throughout this period with no effect on blood pressure or renal blood flow. In separate experiments, administration of enalaprilat after microvascular pO(2) had fallen by 5 mm Hg, resulted in a rise in RBF and pO(2 )within 15 min with pO(2) remaining elevated for up to 60 min post-injection. The angiotensin II AT(1) receptor antagonist, candesartan, had a similar effect to enalaprilat, inducing a rapid and sustained elevation in cortical pO(2). CONCLUSIONS: These studies indicate that blockade of AII raises pO(2 )in the interstitial microvascular compartment of the normal rat kidney. This effect may contribute to the renoprotective action of ACE inhibitors and AII receptor antagonists in slowing the progression of chronic renal diseases.

Angiotensin II↗
PubMed2002

Transcriptional induction of mitogen-activated protein kinase phosphatase 1 by retinoids. Selective roles of nuclear receptors and contribution to the antiapoptotic effect.

All-trans-retinoic acid (t-RA) inhibits hydrogen peroxide (H(2)O(2))-induced apoptosis by inhibiting the c-Jun N-terminal kinase (JNK)-activator protein 1 (AP-1) pathway. In this report, we examined the involvement of mitogen-activated protein kinase phosphatase 1 (MKP-1) in suppression of JNK and the antiapoptotic effect of t-RA and the roles of nuclear receptors in the regulation of MKP-1 by t-RA. We found that not only t-RA, but also a selective agonist of retinoic acid receptor (RAR), a selective agonist of retinoid X receptor (RXR), and a pan-agonist of RAR and RXR all induced MKP-1 at the transcriptional level. Activation of RAR was required for all of these triggering effects, but activation of RXR was required only for the RXR agonist-induced MKP-1 expression. Among the three RAR subtypes, RARalpha and RARgamma, but not RARbeta, mediated the t-RA-induced MKP-1 expression. The antiapoptotic effect of t-RA on H(2)O(2)-induced apoptosis in several cell types was correlated with the inducibility of MKP-1 by t-RA. Inhibition of MKP-1 by vanadate enhanced JNK phosphorylation and attenuated the antiapoptotic effect of t-RA. Furthermore, overexpression of MKP-1 inhibited H(2)O(2)-induced JNK phosphorylation and apoptosis. To our knowledge, this is the first to demonstrate that 1) MKP-1 is inducible by retinoids at the transcriptional level, 2) RXR and individual RAR subtypes have different roles in this process, and 3) the induced MKP-1 plays a significant role in mediating both JNK inhibition and the antiapoptotic effect of t-RA in oxidative stress.

Animals↗
PubMedDate not supplied

Charles Edward Isaacs (1811-1860): exploring the details of nephron structure and function in the post-Bowman period.

Charles Edward Isaacs (1811-1860), an anatomist working in New York, undertook a series of studies which attempted to define the microscopic structure of the nephrons in a variety of species. Given that he published his findings 15 years after William Bowman's seminal paper on the subject, he was able to add only a few of the finer details to the picture. He observed the continuity of the epithelium of the glomerular capsule with that of the proximal tubule and he demonstrated that the glomerular tuft is covered by a layer of epithelial cells. In a series of studies on human renal function he erroneously concluded that the glomerulus must have an excretory function in addition to its filtration function and that diuretics act primarily on the glomerlus. The latter conclusion was based upon observations of substances not currently categorized as being diuretic agents. The absence of a major conceptual advance in the writings of Isaacs probably accounts for that fact that his contribution has been largely forgotten.

History, 19th Century↗
PubMedDate not supplied

Samuel Johnson's illnesses.

The handwritten note of the post-mortem examination of Dr Samuel Johnson resides in the library of the Royal College of Physicians of London. Headed 'asthma' it suggests that he had only one functioning kidney, probably had hypertension, left ventricular hypertrophy and congestive heart failure. This article describes an imaginary presentation by Dr James Wilson, who did the autopsy, and alludes to Johnson's life, and medical history, including impaired vision and hearing, scrofula, abnormal limb movement, gout, abdominal cramps, melancholia and episodes of 'asthma' which were, more than likely to have been episodes of left ventricular failure. Johnson's personality as a demanding patient who took things into his own hands are described based upon reports from his physicians.

Autopsy↗