Pim‐1 as a Therapeutic Target in Lupus Nephritis

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.

Programmed Cell Death Pathways in the Pathogenesis of Systemic Lupus Erythematosus

“…In lupus-prone mice, inhibition of NLRP3 with MCC950 ameliorated proteinuria and renal histologic lesions [102]. Fu et.al also demonstrated that NZB/W F1 mice treated with pim-1 inhibitor AZD1208 showed a suppression of NLRP3 inflammasome activation and a significant reduction in the severity of lupus nephritis [108]. The expression of AIM2, another inflammasome sensing double-stranded nucleic acids in the cytoplasm, was positively correlated with disease severity in patients with SLE and lupus-prone mouse model.…”

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

“…Overexpression of PIM1 appears to influence cancer development in three ways; preventing apoptosis, enhancing cellular proliferation and through promoting genomic instability (75). More specific to kidney research, PIM1 is aberrantly overexpressed in renal cell carcinoma (76) and lupus nephritis (77). In this analysis we identified top-ranked dmCpGs present within the 3' UTR and north shore of PIM1 which resulted in an increase in the FC in individuals with T1D-ESKD.…”

Pim1 kinase positively regulates myoblast behaviors and skeletal muscle regeneration

“…Functionally, studies have well proven that the 34 kDa Pim1 plays a crucial role in a wide range of cell processes and diseases, such as cell proliferation, apoptosis, mitochondrial integrity, cellular senescence, myocardial injury, lupus nephritis and Alzheimer's disease through interaction, stabilization, and phosphorylation of many downstream targets 29,[31][32][33][34][35][36][37][38] . Importantly, as a direct target gene of JAK/STAT-signaling pathway 21,39,40 , Pim1 kinase is also involved in immune regulation and inflammatory response.…”