Cortical interstitial cell interactions induce sensitivity of hydronephrotic kidney to bradykinin

Cortical interstitial cell interactions induce sensitivity of hydronephrotic kidney to bradykinin. The mechanism of the increased prostaglandin production and induction of sensitivity to bradykinin by the cortex of the hydronephrotic rabbit kidney was investigated using tissue culture techniques. Cortical interstitial cells from normal, unilaterally hydronephrotic and contralateral kidneys were grown in tissue culture. Cells derived from hydronephrotic kidneys, but not normal or contralateral, increased PGE2 production when incubated with bradykinin. Of the two cell types, fibroblasts and macrophages, grown from hydronephrotic expiants, neither increased prostaglandin production when grown alone in tissue culture. Recombining the two cell types restored bradykinin responsiveness. Bradykinin responsiveness could be induced in either normal or contralateral cell cultures when macrophages from the hydronephrotic kidney were added to cultures of cells from normal or contralateral cortex. The data indicate unique characteristics of hydronephrotic macrophages are involved in the induction of bradykinin responsiveness in the cortex of the ureter-ligated kidney

Auxin-induced SCFTIR1-Aux/IAA interaction involves stable modification of the SCFTIR1 complex

The plant hormone auxin can regulate gene expression by destabilizing members of the Aux/IAA family of transcriptional repressors. Auxin-induced Aux/IAA degradation requires the protein-ubiquitin ligase SCFTIR1, with auxin acting to enhance the interaction between the Aux/IAAs and SCIFTIR1. SKP1, Cullin, and an F-box-containing protein (SCF)-mediated degradation is an important component of many eukaryotic signaling pathways. In all known cases to date, the interaction between the targets and their cognate SCFs is regulated by signal-induced modification of the target. The mechanism by which auxin promotes the interaction between SCFTIR1 and Aux/IAAs is not understood, but current hypotheses propose auxin-induced phosphorylation, hydroxylation, or proline isomerization of the Aux/IAAs. We found no evidence to support these hypotheses or indeed that auxin induces any stable modification of Aux/IAAs to increase their affinity for SCFTIR1. Instead, we present data suggesting that auxin promotes the SCIFTIR1-Aux/IAA interaction by affecting the SCIF component, TIR1, or proteins tightly associated with it

Renal cortical drug and xenobiotic metabolism following urinary tract obstruction

Renal cortical drug and xenobiotic metabolism following urinary tract obstruction. Renal cortical metabolism of drugs and xenobiotics was assessed with microsomes prepared from normal, contralateral and 4-day postobstructive hydronephrotic kidneys. Microsomal mixed-function oxidase and prostaglandin H synthase systems were determined in control and 3-methylcholanthrene-treated rabbits. Cytochrome P450 content and biphenyl-4-hydroxylase activity but not cytochromec reductase activity were reduced in the hydronephrotic kidney. 3-Methylcholanthrene treatment increased cytochrome P450 content and biphenyl-4-hydroxylase and acetanilide-4-hydroxylase activities in normal, contralateral, and hydronephrotic kidneys. However, even after 3-methylcholanthrene treatment, hydronephrotic kidney cytochrome P450 content and acetanilide-4-hydroxylase activity were not more than 20% of the corresponding normal kidney values. Prostaglandin H synthase metabolism of benzidine was observed in the hydronephrotic kidney but was at the limit of detection in normal or contralateral kidneys with or without 3-methylcholanthrene treatment. Characteristics of benzidine metabolism were consistent with the hydroperoxidase rather than the fatty acid cyclooxygenase activity of prostaglandin H synthase. Therefore, hydronephrosis alters the drug and xenobiotic metabolic profile of the renal cortex from a primarily mixed-function oxidase-dependent system to one with the potential for metabolism by the hydroperoxidase component of prostaglandin H synthase.Métabolisme cortical rénal des médicaments et xénobiotiques après obstruction du tractus urinaire. Le métabolisme cortical rénal de médicaments et de xénobiotiques a été étudié avec des microsomes préparés à partir des reins normaux, controlatérals, et hydronéphrotiques, 4 jours après une obstruction. Les systèmes microsomiaux de fonction oxydase mixte et de prostaglandine H synthétase ont été déterminés chez des lapins contrôles et traités par du 3-méthylcholanthrène. Le contenu en cytochrome P450 et l'activité biphényl-4-hydroxylase, mais non l'activité cytochromec réductase étaient diminués dans le rein hydronéphrotique. Le traitement par le 3-méthylcholanthrène a augmenté le contenu en cytochrome P450 et les activités biphényl-4-hydroxylase et acétanilide-4-hydroxylase chez les reins normaux, controlatérals et hydronéphrotiques. Cependant, même après traitement par le 3-méthylcholanthrène, le contenu en cytochrome P450 du rein hydronéphrotique et son activité acétanilide-4-hydroxylase n'étaient pas de plus de 20% des valeurs dans le rein normaux correspondant. Le métabolisme de la benzidine par la prostaglandine H synthétase était observable dans le rein hydronéphrotique, mais était à la limite de la détection dans les reins normaux ou controlatérals, avec ou sans traitement par le 3-méthylcholanthrène. Les caractéristiques du métabolisme de la benzidine étaient plus compatibles avec l'activité hydroperoxidase qu'avec l'activité cyclooxygénase des acides gras de la prostaglandine H synthétase. Ainsi, l'hydronéphrose altère le profil métabolique des drogues et des xénobiotiques dans le cortex rénal d'un système primitivement dépendant d'une fonction oxydase mixte à un système ayant la capacité de métabolisme par le constituant hydroperoxydase de la prostaglandine H synthétase

Cooxidation of benzidine by renal medullary prostaglandin cyclooxygenase

ABSTRAC

Cyclic AMP metabolism and adenylate cyclase concentration in patients with advanced hepatic cirrhosis

Glucagon was tested for its effect on plasma adenosine 3′,5′-cyclic monophosphate (cyclic AMP), insulin, and glucose in healthy subjects and in patients with advanced cirrhosis of the liver. In the normal subjects, intravenous infusion of glucagon caused a significant increase in plasma cyclic AMP, glucose, and insulin. In advanced cirrhotics, plasma cyclic AMP, glucose, and insulin did not increase. Adenylate cyclase concentration was measured in liver tissue from end stage cirrhotic patients and from brain-dead organ donors whose cardiovascular function was maintained in a stable state. Basal and total adenylate cyclase concentration were not different in the two groups. Adenylate cyclase from the livers of advanced cirrhotics was, however, significantly less responsive to glucagon stimulation than was that from donor livers. Hepatocytes in advanced cirrhosis have abnormal metabolic behavior characterized by abnormal adenylate cyclase-cyclic AMP response to hormonal stimulation. © 1978

Interdependency of Brassinosteroid and Auxin Signaling in Arabidopsis

How growth regulators provoke context-specific signals is a fundamental question in developmental biology. In plants, both auxin and brassinosteroids (BRs) promote cell expansion, and it was thought that they activated this process through independent mechanisms. In this work, we describe a shared auxin:BR pathway required for seedling growth. Genetic, physiological, and genomic analyses demonstrate that response from one pathway requires the function of the other, and that this interdependence does not act at the level of hormone biosynthetic control. Increased auxin levels saturate the BR-stimulated growth response and greatly reduce BR effects on gene expression. Integration of these two pathways is downstream from BES1 and Aux/IAA proteins, the last known regulatory factors acting downstream of each hormone, and is likely to occur directly on the promoters of auxin:BR target genes. We have developed a new approach to identify potential regulatory elements acting in each hormone pathway, as well as in the shared auxin:BR pathway. We show that one element highly overrepresented in the promoters of auxin- and BR-induced genes is responsive to both hormones and requires BR biosynthesis for normal expression. This work fundamentally alters our view of BR and auxin signaling and describes a powerful new approach to identify regulatory elements required for response to specific stimuli

Sl-IAA3, a tomato Aux/IAA at the crossroads of auxin and ethylene signalling involved in differential growth

Whereas the interplay of multiple hormones is essential for most plant developmental processes, the key integrating molecular players remain largely undiscovered or uncharacterized. It is shown here that a member of the tomato auxin/indole-3-acetic acid (Aux/IAA) gene family, Sl-IAA3, intersects the auxin and ethylene signal transduction pathways. Aux/IAA genes encode short-lived transcriptional regulators central to the control of auxin responses. Their functions have been defined primarily by dominant, gain-of-function mutant alleles in Arabidopsis. The Sl-IAA3 gene encodes a nuclear-targeted protein that can repress transcription from auxin-responsive promoters. Sl-IAA3 expression is auxin and ethylene dependent, is regulated on a tight tissue-specific basis, and is associated with tissues undergoing differential growth such as in epinastic petioles and apical hook. Antisense down-regulation of Sl-IAA3 results in auxin and ethylene-related phenotypes, including altered apical dominance, lower auxin sensitivity, exaggerated apical hook curvature in the dark and reduced petiole epinasty in the light. The results provide novel insights into the roles of Aux/IAAs and position the Sl-IAA3 protein at the crossroads of auxin and ethylene signalling in tomato

The Role of Phe82 and Phe351 in Auxin-Induced Substrate Perception by TIR1 Ubiquitin Ligase: A Novel Insight from Molecular Dynamics Simulations

It is well known that Auxin plays a key role in controlling many aspects of plant growth and development. Crystal structures of Transport inhibitor response 1 (TIR1), a true receptor of auxin, were very recently determined for TIR1 alone and in complexes with auxin and different synthetic analogues and an Auxin/Indole-3-Acetic Acid (Aux/IAA) substrate peptide. However, the dynamic conformational changes of the key residues of TIR1 that take place during the auxin and substrate perception by TIR1 and the detailed mechanism of these changes are still unclear. In the present study, various computational techniques were integrated to uncover the detailed molecular mechanism of the auxin and Aux/IAA perception process; these simulations included molecular dynamics (MD) simulations on complexes and the free enzyme, the molecular mechanics Poisson Boltzmann surface area (MM-PBSA) calculations, normal mode analysis, and hydrogen bond energy (HBE) calculations. The computational simulation results provided a reasonable explanation for the structure-activity relationships of auxin and its synthetic analogues in view of energy. In addition, a more detailed model for auxin and Aux/IAA perception was also proposed, indicating that Phe82 and Phe351 played a pivotal role in Aux/IAA perception. Upon auxin binding, Phe82 underwent conformational changes to accommodate the subsequent binding of Aux/IAA. As a result, auxin enhances the TIR1-Aux/IAA interactions by acting as a “molecular glue”. Besides, Phe351 acts as a “fastener” to further improve the substrate binding. The structural and mechanistic insights obtained from the present study will provide valuable clues for the future design of promising auxin analogues