Autotopes and allotopes.
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Anti-Glomerular Basement Membrane Disease↗
Biomedical subjects
Clifford Kashtan
Publications and source records attributed to Clifford Kashtan.
Role of 12-lipoxygenase in the stimulation of p38 mitogen-activated protein kinase and collagen alpha5(IV) in experimental diabetic nephropathy and in glucose-stimulated podocytes.
The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism is implicated in extracellular matrix (ECM) synthesis, but its role in podocytes has not been studied. This study tested whether 12-LO induction by diabetes or by high glucose (HG) in cultured podocytes alters glomerular basement membrane by activating signal transduction pathways culminating in ECM synthesis. Sprague-Dawley rats received an injection of diluent (control [C]) or streptozotocin 65 mg/kg (DM) and were killed at 1 or 4 mo. Glomerular 12-LO mRNA and protein levels were higher in DM than in C glomeruli at 1 and 4 mo, and 12-LO localized predominantly in podocytes. Glomerular p38 mRNA and protein were higher in DM at months 1 and 4, but phospho-p38 mitogen-activated protein (MAPK) was increased only at month 1. Glomerular collagen alpha5(IV)/glutaraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio was increased in DM at month 1 but not at month 4, whereas collagen alpha5(IV) protein was higher at both 1 and 4 mo. Mouse podocytes were cultured in media with 25 mM glucose (HG) with or without the 12-LO inhibitor cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC) or with 5.5 mM glucose + 19.5 mM mannitol (low glucose [LG+M]) for 10 d at 37 degrees C. 12-LO mRNA and protein levels were higher in HG than in LG+M as was the p38 MAPK/GAPDH mRNA ratio. Phospho-p38 MAPK protein but not total p38 MAPK was higher in HG compared with LG+M. Collagen alpha5(IV)/GAPDH mRNA ratio and protein were higher in HG than in LG+M. 12-LO inhibition by CDC decreased HG-induced phospho-p38 MAPK and the phospho-p38/total p38 MAPK ratio, collagen alpha5(IV)/GAPDH mRNA ratio, and collagen alpha5(IV) protein expression. In summary, diabetes in vivo and exposure of podocytes to HG in vitro stimulated 12-LO, p38 MAPK, and collagen alpha5(IV) mRNA and (activated) protein. 12-LO inhibition by CDC diminished the expression of podocyte phospho-p38 MAPK and collagen alpha5(IV) mRNA and protein. These findings implicate 12-LO and the p38 MAPK signaling pathway in the mediation of ECM synthesis by podocytes in diabetes.
Animals↗
Identification of two alternatively spliced forms of human tubulointerstitial nephritis antigen (TIN-Ag).
Tubulointerstitial nephritis antigen (TIN-Ag) is a recently described basement membrane glycoprotein reactive with autoantibodies in some forms of immunologically mediated human tubulointerstitial nephritis. This report presents the complete cDNA and predicted amino acid sequences of two human TIN-Ag mRNA species referred to as TIN1 and TIN2. Translation through the open reading frames of these clones indicates the presence of a signal peptide and putative pre-propeptide. TIN1 additionally contains a characteristic laminin-like epidermal growth factor (EGF) motif and significant homology within the carboxy terminus with the cysteine proteinase family of enzymes. The EGF motif bears important similarities in the positions of cysteines with two motifs in the propeptide of von Willebrand factor. The EGF motif and part of the region that is homologous with the cysteine proteinase family are removed from the TIN2 cDNA. However, the rest of the sequence is identical in these two forms, indicating an alternatively spliced TIN-Ag mRNA product. Both forms contain putative calcium-binding sites. Secondary structure predictions strongly suggest differences between TIN1 and TIN2 leading to the hypothesis that these two forms of TIN-Ag may exhibit differences in their function. Expression studies with appropriate probes demonstrate expression mainly in the kidney and in the intestinal epithelium and lack of expression in other tissues. In the kidney, both TIN1 and TIN2 transcripts are detected, however, TIN1 appears to be the predominant form.
Alternative Splicing↗