Autophagy-lysosome flux failure in diabetic kidney disease: tubular vulnerability and cell-state remodeling
- 1The Second Affiliated Hospital of Anhui University of Chinese Medicine , , ,
- 2School of Clinical Medicine, Anhui University of Chinese Medicine , , ,
Abstract
Diabetic kidney disease (DKD) is conventionally framed as a glomerular microvascular complication but may also involve tubular degradative maladaptation, in which tubular cells progressively fail to clear damaged organelles, lipid droplets, and stress-related cargo through the autophagy–lysosome system. Among tubular compartments, proximal tubular epithelial cells depend particularly heavily on mitochondrial metabolism, endocytic trafficking, vesicular transport, and lysosome-supported proteostasis, making them especially vulnerable to diabetic metabolic stress. This review examines whether autophagy–lysosome failure, encompassing both initiation-level and flux-completion defects, provides a candidate link between adaptive tubular stress responses and maladaptive tubular cell-state remodeling. We appraise therapeutic opportunities for restoring degradative capacity, including standard metabolic and hemodynamic therapies, transcription factor EB (TFEB)- and AMP-activated protein kinase (AMPK)-centered interventions, selective autophagy modulation, and mechanism-guided integrative strategies. We propose a testable, stage-dependent reversibility framework, rather than an established DKD staging system: restoration of autophagy–lysosome flux and lysosomal capacity may be most effective before persistent senescence, ferroptotic vulnerability, and fibrosis become difficult to reverse. Accordingly, we distinguish initiation defects from completion defects using flux-competent criteria and identify the stage-dependent reversibility window as the principal conceptual contribution of this review, rather than a validated clinical staging construct.
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BibTeX
@article{hu2026autophagylysosome,
title = {{Autophagy-lysosome flux failure in diabetic kidney disease: tubular vulnerability and cell-state remodeling}},
author = {Kaili Hu and Kaini Zhou and Aihua Fei and Cangwu Dong},
journal = {Frontiers in endocrinology},
year = {2026},
month = sep,
doi = {10.3389/fendo.2026.1957312},
url = {https://europepmc.org/article/PMC/PMC13662744},
note = {CC BY},
}
RIS
TY - JOUR
TI - Autophagy-lysosome flux failure in diabetic kidney disease: tubular vulnerability and cell-state remodeling
AU - Kaili Hu
AU - Kaini Zhou
AU - Aihua Fei
AU - Cangwu Dong
PY - 2026
DA - 2026/09/30
JO - Frontiers in endocrinology
DO - 10.3389/fendo.2026.1957312
UR - https://europepmc.org/article/PMC/PMC13662744
AB - Diabetic kidney disease (DKD) is conventionally framed as a glomerular microvascular complication but may also involve tubular degradative maladaptation, in which tubular cells progressively fail to clear damaged organelles, lipid droplets, and stress-related cargo through the autophagy–lysosome system. Among tubular compartments, proximal tubular epithelial cells depend particularly heavily on mitochondrial metabolism, endocytic trafficking, vesicular transport, and lysosome-supported proteostasis, making them especially vulnerable to diabetic metabolic stress. This review examines whether autophagy–lysosome failure, encompassing both initiation-level and flux-completion defects, provides a candidate link between adaptive tubular stress responses and maladaptive tubular cell-state remodeling. We appraise therapeutic opportunities for restoring degradative capacity, including standard metabolic and hemodynamic therapies, transcription factor EB (TFEB)- and AMP-activated protein kinase (AMPK)-centered interventions, selective autophagy modulation, and mechanism-guided integrative strategies. We propose a testable, stage-dependent reversibility framework, rather than an established DKD staging system: restoration of autophagy–lysosome flux and lysosomal capacity may be most effective before persistent senescence, ferroptotic vulnerability, and fibrosis become difficult to reverse. Accordingly, we distinguish initiation defects from completion defects using flux-competent criteria and identify the stage-dependent reversibility window as the principal conceptual contribution of this review, rather than a validated clinical staging construct.
SN - 1664-2392
ER -