Background: Tubular senescence is a major determinant of chronic kidney disease (CKD) and identification of potential therapeutic targets involved in senescent tubular epithelial cells has clinical importance. Lysosomal-associated protein transmembrane 5 (LAPTM5) is a key molecule related to T and B cell receptor expression and inflammation. However, the expression pattern of LAPTM5 in the kidney and the contribution of LAPTM5 to the development of CKD keep unknown. Methods: LAPTM5(-/-) mice and tubule specific-LAPTM5 knockout mice were used to examine the role of LAPTM5 in tubular senescence by establishing different experimental mouse CKD models. Results: LAPTM5 expression was significantly induced in the kidney, especially in proximal tubules and distal convoluted tubules, from mice with aristolochic acid nephropathy, bilateral ischemia/reperfusion injury (IRI)-induced CKD or unilateral ureter obstruction (UUO). Tubule-specific deletion of LAPTM5 inhibited senescence of tubular epithelial cells and alleviated tubulointerstitial fibrosis in aged mice. Moreover, LAPTM5 deficiency ameliorated kidney injury and tubular senescence in mice with CKD. Mechanistically, LAPTM5 inhibited ubiquitination of NICD1 by mediating WWP2 lysosomal degradation, then leading to cellular senescence in tubular epithelial cells. Notably, we also observed a higher expression of LAPTM5 in tubules from individuals with CKD and the level of LAPTM5 was correlated with kidney fibrosis and tubular senescence in people with CKD. Conclusions: LAPTM5 contributed to tubular senescence by regulating WWP2/NICD1 signaling pathway and exacerbated kidney injury during the progression of CKD.
[1]Shandong Univ, Sch Basic Med Sci, Dept Pharmacol, Jinan 250012, Peoples R China.
[2]Shandong Univ, Qilu Hosp, Dept Organ Transplantat, Jinan 250012, Peoples R China.
[3]Shandong Univ, Sch Basic Med Sci, Dept Pathol, Jinan 250012, Peoples R China.
[4]Shandong Univ, Hosp 2, Jinan 250033, Peoples R China.
[5]Shandong Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Minist Educ,Key Lab Expt Teratol, Jinan 250012, Peoples R China.
[6]Shandong Univ, Qilu Hosp, Natl Key Lab Innovat & Transformat Luobing Theory, Chinese Minist Educ,Key Lab Cardiovasc Remodeling, Jinan 250012, Peoples R China.
[7]Shandong Univ, Qilu Hosp, Chinese Minist Hlth, Jinan 250012, Peoples R China.
(8.0+极速模式)