EXPLORING THE ROLE OF CELLULAR SENESCENCE IN LUPUS NEPHRITIS

PV017 / #362 Poster Topic: AS02 - Animal Models Background/Purpose Cellular senescence is a physiological process triggered by various stresses, causing cells to enter irreversible cell cycle arrest. These cells nevertheless remain metabolically active, and undergo morphological and functional changes, such as acquisition of a pro-fibrotic and proinflammatory secretome. Cellular senescence has been reported in renal aging and in kidney diseases such as hypertensive nephropathy, IgA nephropathy, and diabetic nephropathy.[1] We previously reported that lupus nephritis (LN) patients with more severe baseline disease and poor long-term outcome exhibit higher levels of cellular senescence (measured using the hallmark marker p16INK4a), in baseline biopsy.[2] We assessed for the presence and time of onset of renal cell senescence in lupus-prone B6.NZMSle1/Sle2/Sle3 (B6. Sle1.2.3) mice, with a view to testing for the effects of senolytic drugs on kidney disease progression in this model. Methods A time-course was performed, with necropsy of 2 C57Bl/6 (B6) and 10 B6.Sle1.2.3 mice, every 2 months from 2 to 12 months. Systemic autoimmunity was assessed by ELISA to measure total IgG and anti-dsDNA IgG in plasma. IgG deposition in kidneys was measured by immunofluorescence. Renal disease was assessed using urine albumin/creatinine ratio and kidney histology (activity and chronicity scores). Cellular senescence in the kidney was assessed by immunohistochemistry for p16Ink4a and senescence-associated β-galactosidase assay. We are now testing the senolytic drug combination dasatinib (5 mg/kg) plus quercetin (50 mg/kg) (DQ) vs vehicle control, in 2 distinct settings: (i) after onset of systemic disease but before onset of any signs of renal disease or renal cell senescence (ie, from 5 months of age until necropsy at 8 months of age); (ii) after onset of renal cell senescence and overt kidney disease (ie, from 8 months of age to necropsy at 10 months of age). Treatment is administered by oral gavage bi-weekly. Systemic and renal disease, as well as cellular senescence, will be assessed as described above. Results We demonstrated, in aged (12-15 month old) B6.Sle1.2.3 lupus-prone mice, that high kidney p16Ink4a positivity is significantly associated with increased proteinuria, histopathological scores, CD8+ T cell infiltration and renal fibrosis. As in patients, p16Ink4a-positivity was not associated with systemic disease parameters or with Ig deposition in the kidney. A time-course showed that systemic disease parameters as well as glomerular IgG deposits increase from 4 months of age in B6.Sle1.2.3 as compared to B6 control mice; kidney disease shows later onset (from 6-8 months of age) and greater heterogeneity. The appearance of p16Ink4a positive cells above B6 levels is observed at 8 months of age in B6.Sle1.2.3 mice.[3] Treatment of a first cohort with DQ is currently ongoing, with preliminary results expected in January 2025. Conclusions Based on the time of onset of renal cell senescence and systemic vs. end-organ disease observed in the B6.Sle1.2.3 mouse model, we are now testing the effect of senolytic therapy (drugs selectively targeting senescent cell anti-apoptotic pathways) on renal disease penetrance and severity. Should renal cell senescence (and the clearance of these cells) prove to have an impact on disease, it could provide a non-immune cell targeting strategy in LN. References: [1.] Valentijn FA. J Cell Commun Signal 2017; 12(1):69-82. [2.] Tilman G. RMD Open 2021;7(3):e001844. [3.] Tilman G. Lupus Sci Med 2023;10(2):e001010.

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