Kidney Week

Abstract: PO0905

Lysophospholipids Predict Fast Decliners with Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Basic Mechanisms
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Yoshioka, Kentaro, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan

Kentaro Yoshioka,

• Hirakawa, Yosuke, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan

Yosuke Hirakawa,

• Kojima, Kensuke, Kyowa Kirin Kabushiki Kaisha Kenkyu Kaihatsu, Chiyoda-ku, Tokyo, Japan

Kensuke Kojima,

• Nangaku, Masaomi, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan

Masaomi Nangaku,

• Inagi, Reiko, University of Tokyo Graduate School of Medicine School of Medicine, Bunkyo-ku, Tokyo, Japan

Reiko Inagi,

Background

In type 2 diabetes, lipid metabolism disorder is frequently complicated due to insufficient insulin secretion and cytokines by visceral fat and regarded as one of the most important risk factors for renal dysfunction. However, specific lipid metabolites that have critical effects on renal dysfunction are not fully understood.

Methods

We performed the metabolomic analysis for patients with diabetic kidney disease (DKD) to identify novel metabolites related to renal prognosis. Plasma and urine biosamples in stage G3 DKD patients (n=135) are collected, and the whole metabolites of them were quantified by capillary electrophoresis mass spectrometry (CE-MS). Significantly fluctuating metabolites in patients with rapidly impaired renal function within 3 years (called “fast decliners”; about 10% in total) were statistically extracted. We also validated the metabolomic candidates with animal DKD model of SDT-fatty rats, or in vitro study using renal proximal tubular cells (HK-2).

Results

In the clinical metabolomic analysis of the biosamples, over 250 metabolites, including lipids, glycates, and amino acids were identified by CE-MS. Among them, specific urinary lysophospholipids (named as LPLs_X) in the fast decliners of DKD were significantly increased. The LPLs_X were moderately correlated with eGFR decline after 3 years (r=0.42, p<0.01). In animal experiments, the level of LPLs_X was also increased in both the urine and the kidney in the subnephrectomized SDT-fatty rats, while we did not see these damages in normal SD rats. In vitro experiments: the exposure of LPLs_X to HK-2 induced apoptosis within 24 h and upregulated pro-apoptotic gene expressions. More physiological changes were investigated in refence to transcriptomic analysis, and we could find that LPLs_X also deranged the lipid metabolism, estimated by intracellular lipid droplet accumulation, and increased the level of mitochondrial reactive oxygen species.

Conclusion

LPLs_X predict “fast decliners” in DKD patients or DKD rats and may have crucial roles in renal tubular damage and dyslipidemia. Our findings provide new insights into the pathophysiological understanding of the relationship between lipid metabolism disorder and DKD progression.

Funding

• Commercial Support – Kyowa Kirin Co., Ltd.