Abstract
Mitochondrial dysfunction is considered as a key mediator in the pathogenesis of diabetic nephropathy (DN). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of DN. In this study, we investigated the role of progranulin (PGRN), a secreted glycoprotein, in mediating mitochondrial homeostasis and its therapeutic potential in DN. We found that the level of PGRN was significantly reduced in the kidney from STZ-induced diabetic mice and patients with biopsy-proven DN compared with healthy controls. In DN model, PGRN-deficient mice aggravated podocyte injury and proteinuria versus wild-type mice. Functionally, PGRN deficiency exacerbated mitochondrial damage and dysfunction in podocytes from diabetic mice. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated high glucose-induced mitochondrial dysfunction in podocytes accompanied by enhanced mitochondrial biogenesis and mitophagy. Inhibition of mitophagy disturbed the protective effects of PGRN in high glucose-induced podocytotoxicity. Mechanistically, we demonstrated that PGRN maintained mitochondrial homeostasis via PGRN-Sirt1-PGC-1α/FoxO1 signaling-mediated mitochondrial biogenesis and mitophagy. Finally, we provided direct evidence for therapeutic potential of PGRN in mice with DN. This study provides new insights into the novel role of PGRN in maintaining mitochondrial homeostasis, suggesting that PGRN may be an innovative therapeutic strategy for treating patients with DN.
Highlights
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the most common cause of end stage renal disease
We observed that the levels of PGRN were significantly reduced in the kidney from diabetic mice and patients with biopsy-proven DN compared with healthy controls
We further found that under the normal conditions, PGRN deficiency in mice had no effects on renal function including the podocyte structure and function, which was consistent with previous studies showing that PGRN knockout mice display normal life expectancy with behavioral deficits and progressive neuropathology but few other recorded phenotypes[26]
Summary
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the most common cause of end stage renal disease. Emerging evidence has shown that podocyte injury is a major prognostic determinant in the development of DN. Zhou et al Cell Death and Disease (2019)10:524 dysfunction takes the center stage in the development and progression of diabetes and its complications[5]. It is remarkably important to search for new therapeutic and preventive strategies aimed at invigorating podocyte mitochondrial function by exploiting key components for mitochondrial homeostasis[9], which involves a network of cellular processes including mitochondrial fission, fusion, biogenesis, and mitophagy. Disruption of these processes results in mitochondrial dysfunction and organ damage. Aberrant mitochondrial morphology and mitochondrial dysfunction are found in high glucose (HG)-treated podocytes due to the decreased levels of mitophagy[10], indicating that mitophagy may play an essential role in the maintaining mitochondrial homeostasis and podocyte function
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