Acute kidney injury

THE JOURNAL OF BIOLOGICAL CHEMISTRY: The Biochemical Behavior of LeadL I. Influence of Calcium, Phosphorus, and Vitamin D on Lead in Blood and Bone

In this review, primary attention is given to the antioxidant (and prooxidant) activity of polyphenols arising from their interactions with iron both in vitro and in vivo. In addition, an overview of oxidative stress and the Fenton reaction is provided, as well as a discussion of the chemistry of iron binding by catecholate, gallate, and semiquinone ligands along with their stability constants, UV–vis spectra, stoichiometries in solution as a function of pH, rates of iron oxidation by O2 upon polyphenol binding, and the published crystal structures for iron–polyphenol complexes. Radical scavenging mechanisms of polyphenols unrelated to iron binding, their interactions with copper, and the prooxidant activity of iron–polyphenol complexes are briefly discussed.

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A Review of the Antioxidant Mechanisms of Polyphenol Compounds Related to Iron Binding

Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation.

Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.

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Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

We cloned the dbl-1 gene, a C. elegans homolog of Drosophila decapentaplegic and vertebrate BMP genes. Loss-of-function mutations in dbl-1 cause markedly reduced body size and defective male copulatory structures. Conversely, dbl-1 overexpression causes markedly increased body size and partly complementary male tail phenotypes, indicating that DBL-1 acts as a dose-dependent regulator of these processes. Evidence from genetic interactions indicates that these effects are mediated by a Smad signaling pathway, for which DBL-1 is a previously unidentified ligand. Our study of the dbl-1 expression pattern suggests a role for neuronal cells in global size regulation as well as male tail patterning.

A bmp homolog acts as a dose-dependent regulator of body size and male tail patterning in caenorhabditis elegans

TGF-beta superfamily ligands play fundamental roles in the development and physiology of diverse animal species. Genetic and genomic analyses in the model organism Caenorhabditis elegans have contributed to the understanding of TGF-beta-related signal transduction mechanisms. In this chapter, I describe the currently characterized TGF-beta-related signals and signal transduction cassettes in C. elegans. Homology searches of the genome identify five TGF-beta-related genes, for which functions have been identified for three. Two of the TGF-beta-related genes, daf-7 and dbl-1, function through conventional signaling pathways. These signaling pathways are comprised of ser/thr kinase receptors, Smads, and transcription co-factors. A third TGF-beta-related gene, unc-129, functions in axonal guidance using novel signaling mechanisms. Thus, TGF-beta-related signaling in C. elegans proceeds via both conserved and novel paradigms that can inform studies in other animal systems.

TGF-beta signaling.

Transforming Growth Factor-β (TGF-β) superfamily ligands regulate many aspects of cell identity, function, and survival in multicellular animals. Genes encoding five TGF-β family members are present in the genome of C. elegans. Two of the ligands, DBL-1 and DAF-7, signal through a canonical receptor-Smad signaling pathway; while a third ligand, UNC-129, interacts with a noncanonical signaling pathway. No function has yet been associated with the remaining two ligands. Here we summarize these signaling pathways and their biological functions.

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TGF-β signaling in C. elegans.

In C. elegans, a TGFbeta-related signaling pathway regulates body size. Loss of function of the signaling ligand (dbl-1), receptors (daf-4 and sma-6) or Smads (sma-2, sma-3 and sma-4) results in viable, but smaller animals because of a reduction in postembryonic growth. We have investigated the tissue specificity of this pathway in body size regulation. We show that different tissues are reduced in size by different proportions, with hypodermal blast cell size most closely proportional to body size. We show that SMA-3 Smad is expressed in pharynx, intestine and hypodermis, as has been previously reported for the type I receptor SMA-6. Furthermore, we find that SMA-3::GFP is nuclear localized in all of these tissues, and that nuclear localization is enhanced by SMA-6 activity. Interestingly, SMA-3 protein accumulation was found to be negatively regulated by the level of Sma/Mab pathway activity. Using genetic mosaic analysis and directed expression of SMA-3, we find that SMA-3 activity in the hypodermis is necessary and sufficient for normal body size. As dbl-1 is expressed primarily in the nervous system, these results suggest a model in which postembryonic growth of hypodermal cells is regulated by TGFbeta-related signaling from the nervous system to the hypodermis.

The expression of TGFβ signal transducers in the hypodermis regulates body size in C. elegans

In the nematode Caenorhabditis elegans, a TGFβ-related signaling pathway regulates body size and male tail morphogenesis. We sought to identify genes encoding components or modifiers of this pathway in a large-scale genetic screen. Remarkably, this screen was able to identify essentially all core components of the TGFβ signaling pathway. Among 34 Small mutants, many mutations disrupt genes encoding recognizable components of the TGFβ pathway: DBL-1 ligand, DAF-4 type II receptor, SMA-6 type I receptor, and SMA-2, SMA-3, and SMA-4 Smads. Moreover, we find that at least 11 additional complementation groups can mutate to the Small phenotype. Four of these 11 genes, sma-9, sma-14, sma-16, and sma-20 affect male tail morphogenesis as well as body size. Two genes, sma-11 and sma-20, also influence regulation of the developmentally arrested dauer larval stage, suggesting a role in a second characterized TGFβ pathway in C. elegans. Other genes may represent tissue-specific factors or parallel pathways for body size control. Because of the conservation of TGFβ signaling pathways, homologs of these genes may be involved in tissue specificity and/or crosstalk of TGFβ pathways in other animals. genesis 35:239–247, 2003. © 2003 Wiley-Liss, Inc.

Cathy Savage-Dunn

Papers

A bmp homolog acts as a dose-dependent regulator of body size and male tail patterning in caenorhabditis elegans

TGF-beta signaling.

TGF-β signaling in C. elegans.

The expression of TGFβ signal transducers in the hypodermis regulates body size in C. elegans

Genetic screen for small body size mutants in C. elegans reveals many TGFβ pathway components