Progranulin alleviates podocyte injury via regulating CAMKK/AMPK-mediated autophagy under diabetic conditions.

Abstract

Podocyte injury is considered a major contributor to the development of diabetic nephropathy (DN). Therefore, identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Recent studies have indicated that autophagy is a key homeostatic mechanism to maintaining podocyte integrity and function. This study was to elucidate the role of progranulin (PGRN), a secreted glycoprotein, in the modulation of podocyte autophagic process and podocyte injury under a diabetic condition. PGRN was downregulated in the kidney from diabetic mice and podocytes under a high-glucose (HG) condition. PGRN deficiency exacerbated the renal dysfunction and glomerular structural alterations. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated HG-induced podocyte injury accompanied by enhanced autophagy. Inhibition of autophagy disturbed the protective effects of PGRN in HG-induced podocytotoxicity. Furthermore, PGRN induced autophagy via the PGRN-CAMKK-AMPK pathway. Collectively, our data identified the protective role of PGRN in podocyte injury via restoring autophagy and activating the CAMKK-AMPK pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy. KEY MESSAGES: • PGRN level is reduced in kidney of diabetic mice and high-glucose-treated podocytes. • PGRN deficiency exacerbates renal injury in diabetic mice. • PGRN protects against high-glucose-induced podocyte injury. • PGRN restores high-glucose-inhibited autophagy in podocytes. • CAMKK-AMPK pathway is required for the protective role of PGRN in podocyte injury.

• Authors: Di Zhou, Meng Zhou, Ziying Wang, Yi Fu, Meng Jia, Xiaojie Wang, Min Liu, Yan Zhang, Yu Sun, Yabin Zhou, Yi Lu, Wei Tang, Fan Yi
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 97 Issue 11 Pg. 1507-1520 (11 2019) ISSN: 1432-1440 [Electronic] Germany
• PMID: 31402399 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Progranulins
• Calcium-Calmodulin-Dependent Protein Kinase Kinase
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Apoptosis (physiology)
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (metabolism)
• Cells, Cultured
• Diabetes Mellitus, Experimental (metabolism)
• Flow Cytometry
• Fluorescent Antibody Technique
• Humans
• Kidney Glomerulus (metabolism)
• Mice
• Mice, Inbred C57BL
• Microscopy, Confocal
• Microscopy, Electron, Transmission
• Podocytes (metabolism)
• Progranulins (genetics, metabolism)
• Signal Transduction (physiology)