13-cis Retinoic Acid Inhibits Development and Progression of Chronic Allograft Nephropathy

Abstract

Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher3443 Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1␣/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-␤1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-␣, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 ؋ 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-B binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and antifibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy.

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

“…Kidneys were evaluated for evidence of acute and chronic vascular (endothelialitis/vasculitis, fibrointimal thickening), glomerular (glomerulitis, glomerulosclerosis) and tubulointerstitial damage (thinning/denudation/necrosis of the tubular epithelia and interstitial edema; tubular atrophy and interstitial fibrosis) on a scale ranging from 0 to 3 as previously described [47,48]. Tubulointerstitial inflammation was judged as 0 À no mononuclear cells in the interstitium, 0.5 À focal mononuclear cell infiltration in the interstitium, 1 À focal mononuclear infiltration in the interstitium with tubulitis, 2 À diffuse mononuclear cell infiltration of the interstitium, 3 À diffuse mononuclear cell infiltration of the interstitium with tubulitis.…”

“…Vascular and glomerular inflammatory infiltrates were scored in an analogous pattern. Scores were calculated as described [47,48].…”

Protocol Transplant Biopsies in Kidney Allografts

“…If evolving fibrosis is detected in the allograft, then therapy with angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (13) can be initiated. Other potential antifibrogenic strategies, including cis-retinoic acid (14), mycophenolate mofetil (13), blockade of endothelin (15), and/or anti-TGF-␤ (16), may be efficacious as well. In addition, potentially fibrogenic medications such as the CNI can be reduced or avoided, if appropriate.…”

Anti-Inflammatory Effects of αv Integrin Antagonism in Acute Kidney Allograft Rejection

“…Kidneys were evaluated for evidence of vascular, glomerular, and tubulointerstitial damage and scored as previously described. 34,35 …”