Kidney international · 2026
Proteinase 3 drives murine diabetic kidney disease by mediating caspase-3-dependent apoptosis of podocytes.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Wan Fangyu, Yang Bei, Li Jufei, Lin Lin, Kong Mengjie, Ni Zheng, Cen Zhikang, Fan Mengqi, Zhang Wen, Liu Shuangxin, Xiao Yang, Zhu Xuejing, Yi Zixuan, Yang Ranyao, Chen Jie, Zhang Yuying, Chen Haiyong, Ge Yuewei, Zang Shufei, Jiang Guozhi, Song Erfei, Xu Aimin, Ye Dewei
Аннотация
INTRODUCTION: Podocytes play a pivotal role in maintaining homeostasis of the glomerular filtration barrier. Podocyte loss represents a critical event that contributes to the development of diabetic kidney disease (DKD). Nonetheless the key mediators and mechanisms underlying DKD-associated podocyte death remain poorly characterized. Proteinase 3 (PR3) is a serine protease with selective high abundance in myeloid cells and pleiotropic effects on the regulation of innate immunity.
METHODS: An experimental DKD model was induced by a combination strategy of uninephrectomy, intraperitoneal injection of streptozocin, and feeding of a high-fat diet in global or podocyte-specific PR3 knockout mice and their controls. Mouse primary podocytes lacking PR3 or conditionally immortalized murine podocytes overexpressing PR3 were incubated with high glucose to trigger apoptosis. Adeno-associated viruses expressing the serine protease inhibitor elafin were injected locally into mouse kidney to inhibit kidney PR3.
RESULTS: PR3 abundance in the kidney was markedly increased, predominantly in podocytes, in mouse models of DKD. Global or podocyte-specific genetic ablation of PR3 significantly attenuated severe proteinuria, mesangial matrix expansion, and podocyte injury in diabetic mice. Mechanistically, the lysates from mouse primary podocytes with high glucose-elicited PR3 enrichment and enhanced enzymatic activity induced cleavage of procaspase-3 and triggered podocyte apoptosis that was substantially alleviated in the presence of genetic ablation or pharmacological inhibition of PR3. Adenovirus-mediated overexpression of PR3 markedly potentiated caspase-3 cleavage and cell apoptosis in conditionally immortalized murine podocytes. In contrast, a lack of PR3 protected against adriamycin-induced podocytopathy in mice, further confirming PR3 as a driving force of podocyte injury. Therapeutically, kidney overexpression of elafin significantly attenuated podocyte loss and other DKD-like traits in mice.
CONCLUSIONS: Our results demonstrate that podocyte-derived PR3 induces caspase-3 cleavage to mediate podocyte apoptosis, thereby potentiating DKD progression, suggesting that pharmacological intervention of podocyte-derived PR3 may represent a promising therapeutic strategy for DKD.
METHODS: An experimental DKD model was induced by a combination strategy of uninephrectomy, intraperitoneal injection of streptozocin, and feeding of a high-fat diet in global or podocyte-specific PR3 knockout mice and their controls. Mouse primary podocytes lacking PR3 or conditionally immortalized murine podocytes overexpressing PR3 were incubated with high glucose to trigger apoptosis. Adeno-associated viruses expressing the serine protease inhibitor elafin were injected locally into mouse kidney to inhibit kidney PR3.
RESULTS: PR3 abundance in the kidney was markedly increased, predominantly in podocytes, in mouse models of DKD. Global or podocyte-specific genetic ablation of PR3 significantly attenuated severe proteinuria, mesangial matrix expansion, and podocyte injury in diabetic mice. Mechanistically, the lysates from mouse primary podocytes with high glucose-elicited PR3 enrichment and enhanced enzymatic activity induced cleavage of procaspase-3 and triggered podocyte apoptosis that was substantially alleviated in the presence of genetic ablation or pharmacological inhibition of PR3. Adenovirus-mediated overexpression of PR3 markedly potentiated caspase-3 cleavage and cell apoptosis in conditionally immortalized murine podocytes. In contrast, a lack of PR3 protected against adriamycin-induced podocytopathy in mice, further confirming PR3 as a driving force of podocyte injury. Therapeutically, kidney overexpression of elafin significantly attenuated podocyte loss and other DKD-like traits in mice.
CONCLUSIONS: Our results demonstrate that podocyte-derived PR3 induces caspase-3 cleavage to mediate podocyte apoptosis, thereby potentiating DKD progression, suggesting that pharmacological intervention of podocyte-derived PR3 may represent a promising therapeutic strategy for DKD.