Mitochondria-associated endoplasmic reticulum membrane (MAM) is emerging as a novel insight into tubular injury in diabetic nephropathy (DN), but the precise mechanism remains unclear. Here, we demonstrate that the expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a critical regulator of MAM formation, is significantly decreased in renal tubules of patients with DN, which is positively correlated with renal function and negatively correlated with degrees of tubulointerstitial lesions. Conditional deletion of Pacs-2 in proximal tubules (PT) aggravates albuminuria and tubular injury in streptozotocin (STZ)-induced diabetic mice. Mitochondrial fragmentation, MAM disruption and defective mitophagy accompanied by altered expression of mitochondrial dynamics and mitophagic protein including DRP1 and BECN1 are observed in tubules from diabetic mice, while these changes are more pronounced in PT-specific Pacs-2 knockout mice. In vitro, overexpression of PACS-2 in HK-2 cells alleviates excessive mitochondrial fission induced by high glucose through blocking mitochondrial recruitment of DRP1, and subsequently restores MAM integrity and enhances mitophagy. Mechanistically, PACS-2 binds to BECN1 and mediates the relocalization of BECN1 to MAM where it promotes the formation of mitophagosome. Together, these data highlight an important but previously unrecognized role of PACS-2 in ameliorating tubular injury in DN by facilitating MAM formation and mitophagy.

NLRP3-mediated inflammation is closely related to the pathological progression of diabetic nephropathy (DN). DsbA-L, an antioxidant enzyme, plays a protective role in a variety of diseases by inhibiting ER stress and regulating metabolism. However, the relationship of DsbA-L with inflammation, especially the NLRP3 inflammasome, has not been examined. In this study, we note that activation of the NLRP3 inflammasome and exacerbated fibrosis were observed in the kidneys of diabetic DsbA-L-knockout mice and were accompanied by decreased phosphorylation of AMP-activated protein kinase (AMPK). Moreover, correlation analysis shows that the phosphorylation of AMPK was negatively correlated with NLRP3 expression and tubular damage. In addition, the decreased AMPK phosphorylation and NLRP3 activation induced by high glucose (HG) in HK-2 cells could be alleviated by the overexpression of DsbA-L. Interestingly, the protective effect of DsbA-L was eliminated after treatment with compound C, a well-known AMPK inhibitor. Our findings suggest that DsbA-L inhibits NLRP3 inflammasome activation by promoting the phosphorylation of AMPK.

The kidney is an energy-consuming organ, and cellular metabolism plays an indispensable role in kidney-related diseases. Caveolin-1 (Cav-1), a multifunctional membrane protein, is the main component of caveolae on the plasma membrane. Caveolae are represented by tiny invaginations that are abundant on the plasma membrane and that serve as a platform to regulate cellular endocytosis, stress responses, and signal transduction. However, caveolae have received increasing attention as a metabolic platform that mediates the endocytosis of albumin, cholesterol, and glucose, participates in cellular metabolic reprogramming and is involved in the progression of kidney disease. It is worth noting that caveolae mainly depend on Cav-1 to perform the abovementioned cellular functions. Furthermore, the mechanism by which Cav-1 regulates cellular metabolism and participates in the pathophysiology of kidney diseases has not been completely elucidated. In this review, we introduce the structure and function of Cav-1 and its functions in regulating cellular metabolism, autophagy, and oxidative stress, focusing on the relationship between Cav-1 in cellular metabolism and kidney disease; in addition, Cav-1 that serves as a potential therapeutic target for treatment of kidney disease is also described.