progranulin alleviates podocyte injury via regulating camkk/ampk-mediated autophagy under diabetic conditions

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 pave the road to new therapeutic modalities for the treatment of diabetic nephropathy. • 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.