Abstract
Kidney disease is one of the most devastating complications of diabetes, and tubular atrophy predicts diabetic kidney disease (DKD) progression to end-stage renal disease. We have proposed that fatty acids bound to albumin contribute to tubular atrophy by inducing lipotoxicity, after filtration across damaged glomeruli, and subsequent proximal tubule reabsorption by a fatty acid transport protein-2-dependent (FATP2-dependent) mechanism. To address this possibility, genetic (Leprdb/db eNOS-/-) and induced (high-fat diet plus low-dose streptozotocin) mouse models of obesity and DKD were bred with global FATP2 gene-deleted mice (Slc27a2) and then phenotyped. DKD-prone mice with the Slc27a2-/- genotype demonstrated normalization of glomerular filtration rate, reduced albuminuria, improved kidney histopathology, and longer life span compared with diabetic Slc27a2+/+ mice. Genetic and induced DKD-prone Slc27a2-/- mice also exhibited markedly reduced fasting plasma glucose, with mean values approaching euglycemia, despite increased obesity and decreased physical activity. Glucose lowering in DKD-prone Slc27a2-/- mice was accompanied by β cell hyperplasia and sustained insulin secretion. Together, our data indicate that FATP2 regulates DKD pathogenesis by a combined lipotoxicity and glucotoxicity (glucolipotoxicity) mechanism.
Highlights
Diabetes affects more than 30 million people in the United States and is a major public health problem due to morbidity and mortality associated with end-organ complications
Histologic data were analyzed by quantitative morphometry and revealed significant tubular atrophy, interstitial fibrosis, and glomerulosclerosis in Slc27a2+/+ Leprdb/db eNOS–/– kidneys, which was improved in kidneys from Slc27a2–/– Leprdb/db eNOS–/– mice (Figure 1, P and Q)
We tested the effect of FATP2-mediated fatty acid uptake in diabetic kidney disease (DKD) pathogenesis using genetic (Leprdb/db eNOS–/–) and acquired (HFD plus low-dose STZ) mouse models of DKD with Slc27a2 deletion
Summary
Diabetes affects more than 30 million people in the United States (https://www.diabetes.org/resources/ statistics/statistics-about-diabetes) and is a major public health problem due to morbidity and mortality associated with end-organ complications. One of the most devastating complications, diabetic kidney disease (DKD), affects as many as 1 in 3 people with diabetes. DKD from type 2 diabetes is by far the most common cause of end-stage renal disease [1], which is only treatable with dialysis or kidney transplantation. Of many DKD biomarkers that have been tested, tubular atrophy and interstitial fibrosis are among the most reliable predictors of progression to end-stage renal disease [8]. Leprdb/db eNOS–/– mice faithfully phenocopy type 2 diabetes and DKD, with decreased glomerular filtration rate (GFR), increased albuminuria, and histologic lesions that include glomerulosclerosis, tubular atrophy due to apoptosis, interstitial fibrosis, and proximal tubule cytoplasmic lipid droplets [12, 13]
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