Accumulation of Senescent Cells in Kidneys is Dependent on Host Immune Status

Abstract

BACKGROUNDCellular senescence is an irreversible cell cycle arrest induced by various mechanisms such as telomere shortening or as a response to various pathophysiologic stressors. This fundamental biological process results in the accumulation of senescent cells which can no longer replicate and regenerate. In the kidney, senescent cells accumulate during natural aging as well as in response to renal injury leading to fibrosis, a chronic inflammatory state and an overall decline in renal function. Clearance of senescent cells is modified by immune surveillance, which in turn, is affected by the immune status of the patient. Our study examines the difference in the accumulation of senescence markers in renal tissue in immunosuppressed states including HIV, Lupus nephritis and post‐transplant in contrast to renal biopsies from non‐immunosuppressed patients (hypertension, diabetes).DESIGNArchived paraffin embedded tissue blocks of kidneys with end‐stage renal disease (ESRD), HIV nephropathy, post‐transplant, diabetes, and hypertension, from the Department of Pathology and Laboratory Medicine are retrieved and subdivided into the three groups: Immunosuppressed states (HIV, lupus and post‐transplant), non‐immunosuppressed states (hypertension, diabetes) and ESRD. Immunohistochemical staining for p16 and p21 were assessed by qualitative scoring (>20% staining taken as positive) including overall staining, as well as in glomerular and interstitial compartments.RESULTSA total of 54 kidney biopsies [14 hypertension, 8 HIV, 7 lupus, 15 transplant (2 without rejection, 3 borderline rejection, 5 acute cellular rejection, 3 antibody mediated rejection and 2 with mixed acute cellular/antibody mediated rejection)] and 10 post‐mortem ESRD cases were included.p16 and p21 staining is observed mainly in the glomerular parietal and tubular epithelium. The pattern of staining observed is diffuse nuclear and cytoplasmic as well as cytoplasmic dot‐like. There is more accumulation of p16 and p21 in immunosuppressed states (HIV, lupus and post‐transplant with rejection) compared to non‐immunosuppressed states. Interestingly, one case with ESRD and lupus also showed strong p16 expression, which was similar to the 2/3 cases with HIV and coexisting lupus.CONCLUSIONClearance of senescent cells is mediated by T cells, macrophages, and natural killer cells. Our results show that there is an increase in senescent cells in immunosuppressed states, which may indicate that immunosuppression and the resulting failure to eliminate senescent cells can contribute to their persistence in tissues and subsequent dysfunction. Percentage of cases expressing p16 and p21 Immune status Diagnosis p16 Percentage (positive cases/Total) p21 Percentage (positive cases/Total) Non‐immunosuppressed Hypertension 21.4 (3/14) 35.7 (5/14) Immunosuppressed HIV 87.5 (7/8) 100 (8/8) Lupus 42.8 (3/7) 100 (7/7) Post‐Tx (no rejection) 0 (0/2) 50 (1/2) Post‐Tx (borderline rejection) 0 (0/3) 0 (0/3) Post‐Tx (acute cellular rejection) 20 (1/5) 40 (2/5) Post‐Tx (Ab mediated rejection) 66.7 (2/3) 100 (3/3) Post‐Tx (cellular+Ab mediated rejection) 50 (1/2) 100 (2/2) Non‐immunosuppressed ESRD 11(1/9) 0 (0/9) Immunosuppressed ESRD 100 (1/1) 0 (0/1) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.