Abstract
Some patients with diabetic kidney disease (DKD) show a fast progression of kidney dysfunction and are known as a "fast decliner" (FD). Therefore, it is critical to understand pathomechanisms specific for fast decline. Here, we performed a comprehensive metabolomic analysis of patients with stage G3 DKD and identified increased urinary lysophosphatidylcholine (LPC) in fast decline. This was confirmed by quantification of urinary LPC using mass spectrometry and identified urinary LPC containing saturated fatty acids palmitic (16:0) and stearic (18:0) acids was increased in FDs. The upsurge in urinary LPC levels was correlated with a decline in estimated glomerular filtration rate after 2.5 years. To clarify a pathogenic role of LPC in FD, we studied an accelerated rat model of DKD and observed an increase in LPC (16:0) and (18:0) levels in the urine and kidney tubulointerstitium as the disease progressed. These findings suggested that local dysregulation of lipid metabolism resulted in excessive accumulation of this LPC species in the kidney. Our invitro studies also confirmed LPC-mediated lipotoxicity in cultured proximal tubular cells. LPC induced accumulation of lipid droplets via activation of peroxisome proliferator-activated receptor-δ followed by upregulation of the lipid droplet membrane protein perilipin 2 and decreased autophagic flux, thereby inducing organelle stress and subsequent apoptosis. Thus, LPC (16:0) and (18:0) may mediate a fast progression of DKD and may serve as a target for novel therapeutic approaches.
Highlights
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan; 2Division of CKD
To determine the molecular mechanisms associated with lipid metabolism in the kidney, we evaluated the expression of genes related to lipid metabolism in diabetic kidney disease (DKD) rat kidney tissues
Immunohistologic staining revealed upregulation of perilipin 2 (PLIN2) in tubular epithelial cells in the cortex (Figure 4h). These results demonstrated that tubular cells were highly susceptible to abnormal lipid metabolism, which may mediate a fast progression of DKD
Summary
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan; 2Division of CKD. To clarify a pathogenic role of LPC in FD, we studied an accelerated rat model of DKD and observed an increase in LPC (16:0) and (18:0) levels in the urine and kidney tubulointerstitium as the disease progressed. These findings suggested that local dysregulation of lipid metabolism resulted in excessive accumulation of this LPC species in the kidney. Our metabolomic analysis of a prospective cohort of patients with diabetic kidney disease (DKD) and animal studies utilizing an accelerated model of DKD revealed changes of urinary lysophosphatidylcholine (LPC) levels in a fast progression of DKD. Analysis of the Global Burden of Disease study data showed that the global incidence of chronic kidney disease increased by 89%, prevalence increased by
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