Enhanced Expression of Janus Kinase–Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy

OBJECTIVE—Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy, whereas tubulointerstitial injury and fibrosis are critical for progression of diabetic nephropathy to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from diabetic nephropathy patients to identify pathways that may be activated in humans but not in murine models of diabetic nephropathy that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis, and kidney failure

A Molecular Signature of Proteinuria in Glomerulonephritis

Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 “albumin-regulated genes” differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n = 25) could be distinguished from those of control subjects (n = 6) based solely upon the expression of these 231 “albumin-regulated genes.” The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that all forms of primary glomerulonephritis (n = 33) can be distinguished from controls (n = 21) based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis

Feedback inhibition of epithelial Na+ channels in Xenopus oocytes does not require G0 or Gi2 proteins

AbstractRegulation of amiloride-sensitive epithelial Na+ channels (ENaC) is a prerequisite for coordination of electrolyte transport in epithelia. Downregulation of Na+ conductance occurs when the intracellular Na+ concentration is increased during reabsorption of electrolytes, known as feedback inhibition. Recent studies have demonstrated the involvement of αG0 and αGi2 proteins in the feedback control of ENaC in mouse salivary duct cells. In this report, we demonstrate that Na+ feedback inhibition is also present in Xenopus oocytes after expression of rat α,β,γ-ENaC. Interfering with intracellular αG0 or αGi2 signaling by coexpression of either constitutively active αG0/αGi2 or dominant negative αG0/αGi2 and by coinjecting sense or antisense oligonucleotides for αG0 had no impact on Na+ feedback. Moreover, no evidence for involvement of the intracellular G protein cascade was found in experiments in which a regulator of G protein signaling (RGS3) or β-adrenergic receptor kinase (βARK) was coexpressed together with α,β,γ-ENaC. Although some experiments suggest the presence of an intracellular Na+ receptor, we may conclude that Na+ feedback in Xenopus oocytes is different from that described for salivary duct cells in that it does not require G protein signaling

Favoriser les régulations biologiques en systèmes agroécologiques de grandes cultures

National audienc