p16^Ink4a, a marker of cellular senescence, is associated with renal disease in the B6.NZMSle1/Sle2/Sle3 mouse model of lupus

Objectives Despite treatment, one-third of patients with lupus nephritis (LN) show a decline in renal function. Prognostic markers of poor outcome as well as novel therapeutic targets are therefore highly sought. We showed that p16(INK4a), a marker of cellular senescence, is observed in baseline kidney biopsies from patients with LN, and is associated with renal disease. Here, we set out to assess for whether these findings are recapitulated in the B6.NZMSle1/Sle2/Sle3 (B6.Sle1.2.3) mouse model of spontaneous lupus.Methods We evaluated the occurrence and time of onset of p16(Ink4a) staining by immunohistochemistry on kidney sections, and tested for its association with multiple renal and systemic disease parameters, fibrosis and CD8(+) T cell infiltration, in two cohorts of B6.Sle1.2.3 mice.Results The presence of p16(Ink4a)-positive cells in kidney was significantly associated with increased urine albumin/creatinine ratio, histopathological scores, CD8(+) T cell infiltration and fibrosis, in both B6.Sle1.2.3 cohorts. In contrast, p16(Ink4a) staining was not associated with systemic disease parameters. A time course showed that systemic disease parameters as well as glomerular IgG deposits appeared in B6.Sle1.2.3 mice by 4 months of age; the appearance of p16(Ink4a)-positive cells occurred later, by 8 months of age, overlapping with renal disease.Conclusion We report, for the first time, the presence of p16(Ink4a)-positive cells, a marker of cellular senescence, in the B6.Sle1.2.3 kidney, and their association with renal disease severity. This provides a preclinical model in which to test for the role of cellular senescence in the pathogenesis of LN, as a potential kidney-intrinsic disease mechanism.