Key result
PACS2 deficiency reduces glomerular endothelial barrier injury, vascular leakage, and fibrosis in diabetic nephropathy models.
Why the study?
Diabetic vascular complications, especially in diabetes mellitus with hyperlipidemia, cause microvascular impairment without effective intervention targets to prevent or reduce serious outcomes.
PACS2 regulates mitochondrial-associated membranes and fatty acid metabolism, and its deletion protects against renal microvascular damage in diabetic models with hyperlipidemia.
PACS2 deletion attenuates diabetic renal microvascular injury in models; hypothesis-generating for human diabetic kidney disease, requiring clinical validation.
Background: The prevalence of diabetic vascular complications is rapidly increasing, especially in the diabetes mellitus with hyperlipidemia. Consistent hyperglycemia and hyperlipidemia impairs microvascular, but lack of effective intervention target to prevention or reduced the risk of serious bad ending. Methods: A mouse model of diabetes combined with hyperlipidemia were established by STZ injection and high fat diet to observe the possible damage of HGHF to renal blood vessels include vascular permeability, fibrosis and subcellular structure. Then, we replicated an in vitro endothelial cell injury model treated by 30mm Glucose and 0.1mm palmitic acid to verify its main functional changes. Proteomics and metabolomics were used to explore the molecular mechanisms behind diabetic microvascular damage. The mechanisms were further verified at siRNA interference and transgenic knockout mice. Results: We found that renal vascular permeability impaired and fibrosis increased significantly in the stz+HFD mice. In human umbilical vein endothelial cells (HUVECs) treated with high glucose/high fat (HGHF), the number of mitochondrial-associated membranes (MAMs) and the expression of phosphofurin acidic cluster sorting protein 2 (PACS2) increased. In particular, gene manipulation of PACS2 altered endothelial cell MAMs. Knocking down PACS2 restored the barrier function of HUVECs. In vivo, knocking out PACS2 ameliorated the kidney injury in diabetic mice induced by streptozotocin and fed with high-fat diet for up to 20 weeks. PACS2-/- mice leaked less vascular Evan’s blue and improved glomerular fibrosis in the kidney tissue of hyperglycemia and hyperlipidemia mouse model. We further observed the reduction of fatty acid β-oxidation (FAO), CPT1α expression, and NADPH production in endothelial cells induced by HGHF. These changes in fatty acid metabolism were rescued by silencing PACS2, but were blocked by the FAO inhibitor, etomoxir. Conclusion: PACS2 impacts the metabolic response of endothelial cells to HGHF through MAMs. Loss of PACS2 expression reduces glomerular endothelial cells barrier injury, induced by VE-Cadherin internalized under HGHF. PACS2 play a metabolism and MAMs regulators in the vascular endothelial cells of diabetes with hyperlipidemia.
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Shu et al. (2021) studied Diabetic nephropathy. PACS2 knockout / knockdown vs. Wildtype / Negative control was evaluated on Renal vascular permeability and glomerular fibrosis. Loss of PACS2 expression reduced glomerular endothelial cell barrier injury, vascular leakage, and fibrosis in in vitro and in vivo models of diabetes with hyperlipidemia.
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