RAGE-mediated interstitial fibrosis in neonatal obstructive nephropathy is independent of NF-κB activation

Abstract

Urinary tract obstruction during nephron development causes tubular apoptosis, tubular atrophy, and interstitial fibrosis. Leukocyte recruitment is critical in the development of obstructive nephropathy leading to interstitial inflammation and renal fibrosis. RAGE, the receptor of advanced glycation end products, is implicated in chronic inflammation and has been recently identified as a novel receptor for the β2-integrin Mac-1, cooperating with ICAM-1 and thereby directly mediating leukocyte recruitment in vivo. Here, we studied the role of RAGE and ICAM-1 in a model of unilateral ureteral obstruction in neonatal mice. Interestingly, the number of infiltrating leukocytes was independent of RAGE and ICAM-1 in the ureteral obstructed neonatal kidney. By contrast, galectin-3, a marker for profibrogenic M2 macrophages, was strongly reduced in ureteral obstructed RAGE and RAGE-Icam1 knockout mice. Snail expression and loss of E-cadherin but not NF-κB activation were attenuated in both knockout models. Epithelial cell cycle arrest at G2/M, which mediates kidney fibrosis, and transforming growth factor-β expression were reduced in ureteral obstructed RAGE knockout mice. Thus, RAGE and ICAM-1 promote renal fibrosis in the developing kidney upon ureteral obstruction. Combined RAGE- and ICAM-1-blocking strategies may prove beneficial in neonatal obstructive nephropathy.

Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

“…57,58 And RAGE has also been connected to fibrogenesis in the lungs 59,60 and kidneys. 61 Thus, there is a consistent body of literature demonstrating that PRRs such as TLRs or RAGE are involved in fibrogenesis, therefore suggesting that DAMPs or other types of ligands besides HMGB1, may exert a pro-fibrotic activity. 62 In this context, HMGB1 certainly acts as DAMP in certain conditions or as an alarmin in other conditions depending on the cell source.…”

“…TLR4 knockout mice are protected against fibrogenesis upon chemically or surgically induced fibrosis in the liver, heart, and lungs, TLR2 knockout mice are preserved toward cardiac fibrosis, and TLR9 has been involved in liver fibrosis . And RAGE has also been connected to fibrogenesis in the lungs and kidneys . Thus, there is a consistent body of literature demonstrating that PRRs such as TLRs or RAGE are involved in fibrogenesis, therefore suggesting that DAMPs or other types of ligands besides HMGB1, may exert a pro‐fibrotic activity .…”

S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy

“…In response to the insult, S100A8/A9 functions as an endogenous ligand which binds to pattern recognition receptors (PRRs), including Toll‐like receptor (TLR)‐4 and the receptor for advanced glycation end‐products (RAGE) . Both receptors are expressed by macrophages and TECs following ureteral obstruction , which can initiate the inflammatory response and are involved in processes related to tissue repair. Also, chronic inflammation may perpetuate tissue injury leading to the development of fibrosis .…”

“…Also, chronic inflammation may perpetuate tissue injury leading to the development of fibrosis . Indeed, several studies have demonstrated that TLR‐4 and RAGE represent key factors of chronic kidney disease (CKD) progression through modulation of interstitial fibrosis . As these receptors are crucial for host defence it might be more interesting to target their ligands instead.…”

Galectin-3 in Renal Pathology: More Than Just an Innocent Bystander?

“…This leukocyte recruitment is mediated by RAGE in cooperation with intercellular adhesion molecule 1. This process is possibly mediated via macrophage-derived galectin-3 secretion, which is a major profibrotic stimulus within the kidney [42] . In mice with CKD induced by UUO, the galectin-3 expression in kidney tissue was significantly higher than in WT mice.…”