This study shows that the mechanisms of long-term I/R injury and immunosuppressants treatment include interstitial inflammation and caspase activation, most clearly demonstrated by the 24 kD active caspase-3.

Abstract. Metabolic acidosis, a common feature of uremia, has a well documented wasting effect on skeletal muscle. In contrast, the effect of metabolic acidosis on adipose tissue is unknown. Serum levels of the adipocyte hormone leptin have been shown to be lower in acidotic uremic rats when compared with uremic controls. This study investigated the effect of acidosis on leptin protein secretion and leptin gene expression. This was studied in vitro by means of 3T3-L1 cultured adipocytes. Leptin secretion was decreased at an acid pH of 7

IgA nephropathy is characterized by mesangial deposition of IgA, mesangial cell proliferation, and extracellular matrix production. Mesangial cells bind IgA, but the identity of all potential receptors involved remains incomplete. The transferrin receptor (CD71) acts as a mesangial cell IgA receptor and its expression is upregulated in many forms of glomerulonephritis, including IgA nephropathy. CD71 is not expressed in healthy glomeruli and blocking CD71 does not completely abrogate mesangial cell IgA binding. Previously we showed that mesangial cells express a receptor that binds the Fc portion of IgA and now report that this receptor is an isoform of β-1,4-galactosyltransferase. A human mesangial cell cDNA library was screened for IgA binding proteins and β-1,4-galactosyltransferase identified. Cell surface expression of the long isoform of β-1,4-galactosyltransferase was shown by flow cytometry and confocal microscopy and confirmed by immunoblotting. Glomerular β-1,4-galactosyltransferase expression was increased in IgA nephropathy. IgA binding and IgA-induced mesangial cell phosphorylation of spleen tyrosine kinase and IL-6 synthesis were inhibited by a panel of β-1,4-galactosyltransferase-specific antibodies, suggesting IgA binds to the catalytic domain of β-1,4-galactosyltransferase. Thus, β-1,4-galactosyltransferase is a constitutively expressed mesangial cell IgA receptor with an important role in both mesangial IgA clearance and the initial response to IgA deposition.

No abstract

We have clearly demonstrated that MCs consistently express an FcalphaR distinct from the myeloid FcalphaR CD89. This novel receptor binds pIgA with high affinity and may therefore mediate the mesangial injury that follows IgA deposition in IgAN. While immunogenically distinct, the mesangial Fcalpha receptor may share some molecular homology with CD89, as mRNA transcripts with partial identity to CD89 were found in all five MC cultures.

Cytokine interactions promote synergistic fibronectin accumulation by mesangial cells.Background. The development of glomerulosclerosis has been associated with the presence of the cytokines transforming growth factor-␤ 1 (TGF-␤ 1 ), tumor necrosis factor-␣ (TNF-␣) and/or interleukin-1␤ (IL-1␤), at some stage in the glomerulus. To better understand the role of these cytokines in the scarring process their effect on rat mesangial cell fibronectin production was investigated.Methods. Mesangial cells were exposed to 10 ng/ml of either TGF-␤ 1 , TNF-␣, or IL-1␤ or to TGF-␤ 1 in combination with TNF-␣ or IL-1␤. Tissue culture supernatants and cell lysates were assayed for fibronectin. Supernatants were also assayed for TGF-␤ 1 . Northern blot analyses probing for fibronectin, transin, TIMP-1 and TGF-␤ 1 were carried out on RNA extracted from mesangial cells exposed to individual and combinations of cytokines.Results. Individually these cytokines were only able to induce modest increases in fibronectin protein levels. However, when mesangial cells were exposed to TGF-␤ 1 in combination with either TNF-␣ or IL-1␤ then fibronectin levels were synergistically up-regulated approximatelly fivefold over unstimulated levels. Northern analysis demonstrated that fibronectin mRNA levels in the combination were also synergistically increased. In contrast, rat transin gene expression in the combinations was reduced to well below levels induced by TNF-␣ and IL-1␤ individually. In addition, synergistic up-regulation of both TGF-␤ 1 protein and message by the cytokine combinations was also observed. TGF-␤ 1 :TNF-␣ and TGF-␤ 1 : IL-1␤ induced additive increases in TIMP-1 (tissue inhibitor of metalloproteinases-1) mRNA levels.Conclusions. These data illustrate that complex interactions can occur between cytokines within the glomerulus modulating both matrix synthetic and degradation pathways. These could initiate the scarring process and the development of glomerulosclerosis.

These data suggest that the pro-fibrotic effect of glucose dialysate on HPMC is mediated through stimulation of TGF-beta, which promotes FN gene expression and protein production.

These results suggest that ACE-I-induced renoprotection, in the context of macrophage-stimulated mesangial cell scarring, is mediated, at least in part, via the actions of bradykinin.