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Lipoprotein lipase (LPL) is an enzyme that catalyzes the hydrolysis of circulating triglyceride and the transport of fatty acids into cells. Its activity is positively regulated by insulin, and insulin resistance is associated with low LPL activity and subsequent hypertriglyceridemia. The involvement of hypertriglyceridemia in chronic kidney disease (CKD) is still under the debate in a clinical setting. Therefore, we aimed to study the role of hypertriglyceridemia in the disease using mice with systemic or renal-specific LPL deficiency. Systemic LPL deficiency was characterized by hypertriglyceridemia, but not renal injury or dyslipidemia-related conditions, such as fatty liver. Furthermore, the LPL deficiency-induced hypertriglyceridemia was not associated with a worsening of the CKD phenotype or atherosclerosis, even when CKD was induced by 5/6 nephrectomy. Next, because LPL-mediated fatty acid uptake may be important for energy metabolism in proximal tubular epithelial cells (PTECs), the role of renal LPL in renal physiology was studied by generating mice lacking LPL specifically in PTECs. These mice showed no abnormalities in their histology or renal reabsorption of micro molecules. These findings suggest that systemic and renal lipid abnormalities caused by LPL deficiency do not cause or worsen the development of renal injury, and provide novel insight regarding the potential role of lipotoxicity in the pathogenesis of obesity-related kidney injury. • Adult mice with systemic lipoprotein lipase (LPL) deficiency were generated. • Systemic LPL deficiency causes severe hypertriglyceridemia. • Systemic LPL deficiency neither causes nor worsens kidney injury. • LPL deficiency-induced dyslipidemia is not related to atherosclerosis development. • Renal LPL is not necessary for normal renal physiology. [ABSTRACT FROM AUTHOR]

Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with higher energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARα-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes. [ABSTRACT FROM AUTHOR]

To examine the cell-protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes, we analyzed the renal phenotype of tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (iPodo-Atg5−/−) mice with experimental endothelial dysfunction. In both control and iPodo-Atg5−/− mice, high fat diet (HFD) feeding induced glomerular endothelial damage characterized by decreased urinary nitric oxide (NO) excretion, collapsed endothelial fenestrae, and reduced endothelial glycocalyx. HFD-fed control mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed iPodo-Atg5−/− mice developed massive albuminuria accompanied by severe podocyte injury that was observed predominantly in podocytes adjacent to damaged endothelial cells by scanning electron microscopy. Although podocyte-specific autophagy deficiency did not affect endothelial NO synthase deficiency-associated albuminuria, it markedly exacerbated albuminuria and severe podocyte morphological damage when the damage was induced by intravenous neuraminidase injection to remove glycocalyx from the endothelial surface. Furthermore, endoplasmic reticulum stress was accelerated in podocytes of iPodo-Atg5−/− mice stimulated with neuraminidase, and treatment with molecular chaperone tauroursodeoxycholic acid improved neuraminidase-induced severe albuminuria and podocyte injury. In conclusion, podocyte autophagy plays a renoprotective role against diabetes-related structural endothelial damage, providing an additional insight into the pathogenesis of massive proteinuria in diabetic nephropathy. • Diabetes causes functional and structural glomerular endothelial damage. • Autophagy protects podocytes against structural glomerular endothelial damage. • Enhanced ER stress is involved in autophagy deficiency-mediated podocyte damage. [ABSTRACT FROM AUTHOR]