Pharmacological and genetic inhibition of downstream targets of p38 MAPK in experimental nephrotic syndrome

Xiaojing Nie, Melinda A. Chanley, Ruma Pengal, David Thomas, Shipra Agrawal, William E. Smoyer

Research output: Contribution to journalArticle

Abstract

The p38 MAPK pathway plays a crucial role in various glomerulopathies, with activation being associated with disease and inhibition being associated with disease amelioration. We hypothesized that the downstream targets of p38 MAPK, MAPK-activated protein kinase 2 and/or 3 (MK2 and/or MK3), play an important role in mediating injury in experimental nephrotic syndrome via their actions on their downstream substrates heat shock protein B1 (HSPB1) and cyclooxygenase-2 (COX-2). To test this hypothesis, the effects of both pharmacological and genetic inhibition of MK2 and MK3 were examined in mouse adriamycin (ADR) and rat puromycin aminonucleoside (PAN) nephropathy models. MK2–/–, MK3–/–, and MK2–/–MK3–/– mice were generated in the Sv129 background and subjected to ADR-induced nephropathy. MK2 and MK3 protein expression was completely abrogated in the respective knockout genotypes, and massive proteinuria and renal histopathological changes developed after ADR treatment. Furthermore, renal cortical HSPB1 was induced in all four genotypes by day 21, but HSPB1 was activated only in the wild-type and MK3–/– mice. Expression of the stress proteins HSPB8 and glucose-regulated protein 78 (GRP78) remained unaltered across all genotypes. Finally, while MK2 and/or MK3-knockout downregulated the proinflammatory enzyme COX-2, ADR significantly induced renal cortical COX-2 only in MK2–/– mice. Additionally, pharmacological MK2 inhibition with PF-318 during PAN-induced nephropathy did not result in significant proteinuria reduction in rats. Together, these data suggest that while the inhibition of MK2 and/or MK3 regulates the renal stress response, our currently available approaches are not yet able to safely and effectively reduce proteinuria in experimental nephrotic syndrome and that other p38MAPK downstream targets should also be considered to improve the future treatment of glomerular disease.

Original languageEnglish (US)
Pages (from-to)F602-F613
JournalAmerican Journal of Physiology - Renal Physiology
Volume314
Issue number4
DOIs
StatePublished - Apr 1 2018

Keywords

  • Glomerular disease
  • Inhibition
  • MAPK
  • MK2
  • MK3
  • Nephrotic syndrome
  • P38
  • Proteinuria

ASJC Scopus subject areas

  • Physiology
  • Urology

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