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

Abstract

SummaryDespite advances in our understanding of the mechanisms underlying the progression of chronic kidney disease and the development of fibrosis, only limited efficacious therapies exist. The calcium binding protein S100A8/A9 is a damage‐associated molecular pattern which can activate Toll‐like receptor (TLR)‐4 or receptor for advanced glycation end‐products (RAGE). Activation of these receptors is involved in the progression of renal fibrosis; however, the role of S100A8/A9 herein remains unknown. Therefore, we analysed S100A8/A9 expression in patients and mice with obstructive nephropathy and subjected wild‐type and S100A9 knock‐out mice lacking the heterodimer S100A8/A9 to unilateral ureteral obstruction (UUO). We found profound S100A8/A9 expression in granulocytes that infiltrated human and murine kidney, together with enhanced renal expression over time, following UUO. S100A9 KO mice were protected from UUO‐induced renal fibrosis, independently of leucocyte infiltration and inflammation. Loss of S100A8/A9 protected tubular epithelial cells from UUO‐induced apoptosis and critical epithelial–mesenchymal transition steps. In‐vitro studies revealed S100A8/A9 as a novel mediator of epithelial cell injury through loss of cell polarity, cell cycle arrest and subsequent cell death. In conclusion, we demonstrate that S100A8/A9 mediates renal damage and fibrosis, presumably through loss of tubular epithelial cell contacts and irreversible damage. Suppression of S100A8/A9 could be a therapeutic strategy to halt renal fibrosis in patients with chronic kidney disease.

Molecular phenotyping of rejection-related changes in mucosal biopsies from lung transplants

“…The top 20 R4 injury transcripts (Table S7) had their highest expression in A4 injury biopsies and were primarily expressed in macrophages and/or monocytes (and probably neutrophils – see Discussion). Two were DAMPs, including S100A8 , a typical acute inflammation transcript . Similarly, the top 20 PC3‐associated transcripts (Table S8) had their highest expression in the A4 injury biopsies.…”

“…Two were DAMPs, including S100A8, a typical acute inflammation transcript. 27 Similarly, the top 20 PC3-associated transcripts (Table S8) had their highest expression in the A4 injury biopsies.…”

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

“…Fibrosis in its own right can be conceptualized as a trade-off imbalance between extracellular matrix production and degradation that occurs in almost all types of chronic disease [ 57 , 58 ]. Several pathways and mechanisms have been described in the pathogenesis of fibrosis [ 58 , 59 , 60 , 61 , 62 ]. Recent studies have examined the role of the NKA signaling in mediating organ fibrosis.…”

Angiotensin II triggers RIPK3-MLKL-mediated necroptosis by activating the Fas/FasL signaling pathway in renal tubular cells

“…Apoptosis has been suggested to play a critical role in the loss of renal tubular epithelial cells in a previous study [33,34]. In our previous study, Apoptotic renal tubular epithelial cells and cleaved caspase-3 expression were enhanced in kidney tissue from SNx rats, and this effect was inhibited by zVAD [5].…”