RANTES Deficiency Attenuates Autoantibody-Induced Glomerulonephritis

Abstract

Experimental autoimmune nephritis in mice and spontaneous lupus nephritis are both associated with elevated expression of several chemokines in the kidneys. Nevertheless, the role that different chemokines play in mediating renal inflammation is far from complete. This study focuses on elucidating the functional role of RANTES, a chemokine that has been noted to be hyper-expressed within the kidneys, both in experimental renal disease as well as in spontaneous lupus nephritis. To elucidate if RANTES was essential for immune-mediated glomerulonephritis, DBA/1 mice that are highly sensitive to nephrotoxic serum nephritis were rendered RANTES-deficient and then tested for disease susceptibility. Nephritis-sensitive DBA/1 mice expressed more RANTES within the diseased kidneys. Compared to wild-type DBA/1 mice, RANTES-deficient DBA/1 mice developed significantly less proteinuria, azotemia, and renal inflammation, with reduced crescent formation and tubulo-interstitial nephritis. These findings indicate that RANTES ablation attenuates immune-mediated nephritis and suggest that this chemokine could be a potential therapeutic target in these diseases.

The Fli-1 Transcription Factor Regulates the Expression of CCL5/RANTES

“…CCL5 expression in the glomerulus has also been documented previously (6, 10, 22–24). Thus, we chose to investigate if a disruption in Fli-1 expression affects CCL5 production in vitro ; we performed transfection studies using Fli-1 specific siRNA and negative control siRNA in murine endothelial MS1 cells.…”

“…A variety of renal diseases have been linked to the CCL5 gene (21) and its’ expression has been documented in the kidney cortex, glomerulus, and renal tubular epithelial cells (5, 6, 10, 20, 22–24). Analysis of microarray data from glomerular gene expression in MRL/ lpr mice, a murine model of lupus, with active lupus nephritis demonstrated a profound up-regulation of CCL5 mRNA (24).…”

“…In MRL/ lpr mice, CCL5 gene expression increased with disease progression and promoted renal injury through the recruitment of macrophages, CD4+ and CD8+ T cells to the kidney, particularly the area surrounding the glomeruli (20). A mouse model that exhibits autoimmune nephrotoxic serum nephritis was shown to have increased CCL5 mRNA expression in diseased mice, whereas proteinuria was decreased in CCL5 deficient mice and milder versions of glomerulonephritis observed (22). Increased CCL5 expression has been detected in the serum of patients with SLE, although correlation with patients’ SLEDAI (SLE disease activity index) scores appears to depend on further classification of the disease (17, 18).…”

Glutathione S-transferase Mu 2-transduced mesenchymal stem cells ameliorated anti-glomerular basement membrane antibody-induced glomerulonephritis by inhibiting oxidation and inflammation

“…Anti-GBM-GN has been used as a model for the study of lupus nephritis because the two conditions share some common molecular pathways [11]. Our previous study showed that anti-GBM antibody challenge induced severe GN in some mouse strains such as 129/svj, DBA1, and NZW, whereas some other strains, such as B6 and BALB/c, were resistant to anti-GBM challenge, exhibiting no or very mild GN [12].…”

Biomarkers for Kidney Involvement in Pediatric Lupus

“…RANTES is an important chemotactic molecule for T cells and plays an active role in leukocyte recruitment and the development of LN, as demonstrated in a RANTES-defficient murine model, which developed milder renal disease upon induction of an immune complex-mediated nephritis [127]. Along those lines, urinary CD4 + T cells were recently described as an additional tool for the identification of LN in adult SLE patients [128].…”