Apoptosis signal-regulating kinase 1 inhibition attenuates cardiac hypertrophy and cardiorenal fibrosis induced by uremic toxins: Implications for cardiorenal syndrome

PLoS One. 2017 Nov 6;12(11):e0187459. doi: 10.1371/journal.pone.0187459. eCollection 2017.

Abstract

Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cresol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by 3H-leucine and 3H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro-hypertrophic (α-skeletal muscle actin and β-MHC) and pro-fibrotic genes (TGF-β1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-κB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein-bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy.

MeSH terms

  • Animals
  • Cardio-Renal Syndrome / pathology*
  • Cardiomegaly / prevention & control*
  • Cells, Cultured
  • Cresols / pharmacology
  • Fibrosis
  • Indican / pharmacology
  • MAP Kinase Kinase Kinase 5 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Sulfuric Acid Esters / pharmacology
  • Toxins, Biological / toxicity*

Substances

  • Cresols
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Sulfuric Acid Esters
  • Toxins, Biological
  • uremia middle molecule toxins
  • 4-cresol sulfate
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Indican

Grants and funding

This research was supported by National Health and Medical Research Council of Australia [Program Grants 546272 and 1092642 (to HK) and Project Grant 1087355 (to BHW)]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.