Dysregulation of low-density lipoprotein receptor contributes to podocyte injuries in diabetic nephropathy.

Abstract

Dyslipidemia plays crucial roles in the progression of diabetic nephropathy (DN). This study investigated the effects of high glucose on lipid accumulation in podocytes and explored its underlying mechanisms. Male db/m and db/db mice were fed a normal chow diet for 8 wk. Immortalised mouse podocytes were treated with or without high glucose for 24 h. The changes to the morphology and ultramicrostructures of the kidneys in mice were examined using pathological staining and electron microscopy. Intracellular lipid accumulation was evaluated by Oil Red O staining and a free cholesterol quantitative assay. The expressions of the molecules involved in low-density lipoprotein receptor (LDLr) pathway and podocyte injury were examined using immunofluorescent staining, real-time PCR, and Western blot. There were increased levels of plasma lipid, serum creatinine, and proteinuria in db/db mice compared with db/m mice. Moreover, there was significant mesangial matrix expansion, basement membrane thickening, podocyte foot process effacement, and phenotypic alteration in the db/db group. Additionally, lipid accumulation in the kidneys of db/db mice was increased due to increased protein expressions of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein, and SREBP-2. These effects were further confirmed by in vitro studies. Interestingly, the treatment with LDLr siRNA inhibited lipid accumulation in podocytes and decreased the protein expression of molecules associated with phenotypic alteration in podocytes. High glucose disrupted LDLr feedback regulation in podocytes, which may cause intracellular lipid accumulation and alteration of podocyte phenotype, thereby accelerating DN progression.

• Authors: Yang Zhang, Kun Ling Ma, Jing Liu, Yu Wu, Ze Bo Hu, Liang Liu, Bi Cheng Liu
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 308 Issue 12 Pg. E1140-8 (Jun 15 2015) ISSN: 1522-1555 [Electronic] United States
• PMID: 25921580 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• RNA, Small Interfering
• Receptors, LDL
• Glucose

Topics

• Animals
• Cells, Cultured
• Diabetes Mellitus, Experimental (complications, genetics, metabolism)
• Diabetic Nephropathies (genetics, metabolism, pathology)
• Disease Progression
• Gene Expression Regulation (drug effects)
• Glucose (metabolism, pharmacology)
• Hyperglycemia (pathology)
• Hyperlipidemias (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (complications, genetics, metabolism)
• Podocytes (drug effects, metabolism, pathology)
• RNA, Small Interfering (pharmacology)
• Receptors, LDL (genetics, metabolism)