Cholesterol transport proteins and diabetic nephropathy

Abstract

Aims: Lipid accumulation in the kidney has been shown to accelerate renal injury. Intracellular accumulation of lipids may be caused by alterations in synthesis as well as lipid uptake and efflux. Cellular cholesterol efflux is mediated by specific cholesterol transport proteins including scavenger receptor class B type 1 (SR-BI), adenosine triphosphate binding cassette transporter G1 (ABCG1) and ABCA1. We have investigated whether there are changes in cellular cholesterol transport proteins in diabetic nephropathy.

Methods: Protein expression of SR-BI, ABCG1 and ABCA1 was determined in human mesangial cells and tubular cells cultured under normal or high glucose conditions in vitro. Renal expression of these cholesterol transporters was examined in mice with streptozotocin-induced type 1 diabetes.

Results: SR-BI, ABCG1 and ABCA1 were expressed in both human mesangial cells and tubular cells. Incubation of mesangial cells and tubular cells with HDL stimulated cellular cholesterol efflux by 2.7 ± 0.2 fold, p<0.01 and 2.1 ± 0.3 fold, p<0.05 respectively, whereas incubation with apolipoprotein A1 had a lesser effect. In vitro, hyperglycemia significantly reduced the expression of all three cholesterol transporters in a dose-dependent manner. In vivo studies showed that renal cholesterol (1.5 ± 0.2 fold, p<0.01) and triglyceride content (2.9 ± 0.2 fold, p<0.01) was increased in diabetic mice with nephropathy compared to non-diabetic control mice. This was associated with a significant reduction in the protein expression of ABCA1 (59 ± 16%, p<0.05), ABCG1 (73 ± 14%, p<0.05) and SR-BI (58 ± 10%, p<0.01) in the kidneys. Glomerular abnormalities and tubulo-interstitial changes were noted in mice with diabetic nephropathy and immunohistological examination showed that there was a marked reduction in all three cholesterol transporters particularly in the renal tubules.

Conclusion: Reduced renal expression of SR-BI, ABCG1 and ABCA1 was associated with diabetic nephropathy. Defects in cholesterol export pathway in renal cells could promote cholesterol accumulation and might contribute to the development of diabetic nephropathy.

Acknowledgement: supported by funding from the Hong Kong Research Grants Council Research Fund (HKU 776709M).

No conflict of interest