Premature renal epithelial cell senescence promoted by LXN/Rps3/p53 signaling pathway activation increases calcium oxalate crystal deposition by altering macrophage polarization

Maolin Chu^1*Suna Jiang²Jiawei Xue²Wenjing Li²Guanhua Jing³Hongying Li²Juan Zhang^2*Hai Wan Xu^1*

• ¹The Second Affiliated Hospital of Harbin Medical University, Harbin, China
• ²First Affiliated Hospital of Harbin Medical University, Harbin, China
• ³Henan Provincial People's Hospital, Zhengzhou, China

Premature senescence of renal tubular epithelial cells (RTECs) can be caused by oxidative stress related to calcium oxalate (CaOx) kidney stones (KSs), but the role and mechanisms of cellular senescence of RTECs in the pathogenesis of kidney stones have not been fully determined. Macrophages, the most prevalent leucocyte found in nephrolithiasis, have been implicated in the pathogenesis of kidney stones. Here, we examined whether CaOx could induce senescence in human kidney (HK)-2 cells, a proximal tubular renal cell line, and the effect of RTEC senescence on renal macrophages during disease progression. The onset of RTEC senescence was increased after treatment with oxalate (Ox), and the increase in RTEC senescence was reduced by fisetin treatment. Interestingly, the changes in proinflammatory M1-like phenotype polarization induced by culture medium from HK-2 cells treated with Ox+/-fisetin were consistent with the proportion of senescent HK-2 cells cultured. Furthermore, reducing cellular LXN/Rps3/p53 signaling significantly decreased senescence-associated secretory phenotype (SASP) factors in the culture medium and simultaneously abolished M1-like phenotype macrophage polarization. More importantly, silencing renal LXN reduced RTEC senescence and M1-like phenotype macrophage polarization and consequently decreased intrarenal CaOx crystal deposition in a rat kidney stone model. Thus, our results demonstrate that kidney macrophage phenotype changes are related, at least in part, to RTEC senescence, and a strategy to modulate the cellular senescence of RTECs is promising as a new target for immunotherapy to treat nephrolithiasis and other age-related diseases.