Inhibition of Hippo signaling pathway preserves renal mitochondrial quality control homeostasis and protects against diabetic kidney diseases

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Therefore, efforts to understand DKD pathophysiology and prevent its development are highly warranted. Here, we analyzed renal cortex from healthy mice, diabetic mice, and diabetic mice treated with the Hippo signaling pathway inhibitor XMU-MP-1. Our study first confirmed that XMU-MP-1 improved DKD in type 2 diabetic mice induced by high-fat diet feeding and intraperitoneal injection of streptozotocin. Through RNA-sequencing of isolated renal cortex, we found that activation of the Hippo signaling pathway, chemokine signaling pathway and cell activation involved in immune response were positively associated with the progression of DKD, while mitochondrion organization was negatively associated with the development of DKD. By contrast, administration of XMU-MP-1 partly suppressed the irritation of chemokine signaling pathway, and organ or tissue specific immune response, but preserved mitochondrion organization within renal cortex of DKD. In vitro, cell culture of immortalized renal tubule cells revealed that overexpression of yes-associated protein 1, the downstream core mediator of the Hippo signaling pathway, reduced high glucose and palmitic acid-induced tubule cell impairment by improving the maintenance of mitobiogenesis and mitophagy. Overall, our data emphasize that the renal protective effects of suppressing Hippo signaling pathway are likely through preserving the mitochondrial quality control homeostasis in tubule cells. Overall design: The mice were categorized into four groups: (1) Mice on a normal diet (Normal diet + Citrate buffer + Vehicle) group (n=6); (2) Mice on a normal diet with XMU-MP-1 administration (Normal diet + Citrate buffer + XMU-MP-1) group (n=6); (3) Mice on a high-fat diet with streptozotocin (STZ) administration (High-fat diet + STZ + Vehicle) group (n=6); and (4) Mice on a high-fat diet with STZ and XMU-MP-1 administration (High-fat diet + STZ + XMU-MP-1) group (n=6). XMU-MP-1 (Selleck, Shanghai, China), dissolved in solvent (2% DMSO [MP Biomedicals, Solon, OH, USA], 30% PEG300 [Selleck], 2% Tween80 [Selleck], and ddH2O), was administered intraperitoneally at a dosage of 1 mg/kg body weight every two days to wild-type diabetic mice induced by a combination of high-fat diet feeding and intraperitoneal streptozotocin injection. The solvent of XMU-MP-1 was used as vehicle control in this experiment. XMU-MP-1 treatment commenced two weeks post intraperitoneal streptozotocin injection and continued for an additional 12 weeks. At the conclusion of the experiments, mice were anesthetized and humanely euthanized by cervical dislocation, and mice samples were collected for further analysis.