Pim-1 as a Therapeutic Target in Lupus Nephritis

Arthritis Rheumatol. 2019 Aug;71(8):1308-1318. doi: 10.1002/art.40863. Epub 2019 Jul 2.

Abstract

Objective: Lupus nephritis (LN) is a major determinant of morbidity and mortality in systemic lupus erythematosus (SLE). Pim-1 regulates lymphocyte proliferation and activation. The role of Pim-1 in autoimmune disease remains unclear. This study was undertaken to test the hypothesis that inhibition of Pim-1 would have therapeutic potential in patients with LN.

Methods: Pim-1 expression was analyzed in lupus-prone (NZB × NZW)F1 mice (n = 6), human peripheral blood mononuclear cells (PBMCs) from SLE patients (n = 10), and glomeruli from patients with LN (n = 8). The therapeutic effect of the Pim-1 inhibitor AZD1208 was assessed in the same murine lupus model (n = 10 mice per group). In vitro analysis was conducted to explore the mechanisms of action of Pim-1 in mouse and human podocytes after Pim-1 expression had been induced by anti-double-stranded DNA (anti-dsDNA) antibody-positive serum. Finally, MRL/lpr mice were used to confirm the therapeutic effects of Pim-1 inhibition in vivo (n = 10 mice per group).

Results: Up-regulation of Pim-1 was seen in renal lysates from diseased (NZB × NZW)F1 mice and in PBMCs from patients with SLE and renal biopsy tissue from patients with LN, relative to their control counterparts (each P < 0.05). The Pim-1 inhibitor AZD1208 reduced the severity of proteinuria, glomerulonephritis, renal immune complex deposits, and serum anti-dsDNA antibody levels, concomitant with the suppression of NFATc1 expression and NLRP3 inflammasome activation, in diseased (NZB × NZW)F1 mice (each P < 0.05 versus controls). Moreover, in mouse and human podocytes, Pim-1 knockdown with targeted small interfering RNA (siRNA) suppressed NFATc1 and NLRP3 inflammasome signaling in the presence of anti-dsDNA-positive serum (each P < 0.05 versus control siRNA). Mechanistically, Pim-1 modulated NLRP3 inflammasome activation through intracellular Ca2+ (P < 0.05 versus normal controls). The therapeutic effect of Pim-1 blockade was replicated in MRL/lpr mice.

Conclusion: These data identify Pim-1 as a critical regulator of LN pathogenesis in patients with SLE. Targeting of the Pim-1/NFATc1/NLRP3 pathway might therefore have therapeutic potential in human LN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / immunology
  • Cell Proliferation / drug effects*
  • Disease Models, Animal
  • Humans
  • Inflammasomes / drug effects
  • Kidney / cytology
  • Kidney Glomerulus / metabolism
  • Leukocytes, Mononuclear
  • Lupus Erythematosus, Systemic / complications*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Nephritis / drug therapy*
  • Lupus Nephritis / immunology
  • Lymphocyte Activation / drug effects*
  • Mice
  • Mice, Inbred MRL lpr
  • NFATC Transcription Factors / drug effects
  • NLR Family, Pyrin Domain-Containing 3 Protein / drug effects
  • Podocytes / metabolism
  • Proto-Oncogene Proteins c-pim-1 / immunology
  • Proto-Oncogene Proteins c-pim-1 / pharmacology*
  • Signal Transduction / drug effects

Substances

  • Antibodies, Antinuclear
  • Inflammasomes
  • NFATC Transcription Factors
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Proto-Oncogene Proteins c-pim-1