Abstract
The commonly prescribed Tangshen Formula (TSF) is a traditional Chinese formulation that has been shown to reduce plasma lipid metabolism and proteinuria and improve the estimated glomerular filtration rate (eGFR) in patients with diabetic kidney disease. This study investigated the underlying mechanism whereby TSF regulates renal lipid accumulation and ameliorates diabetic renal injuries in spontaneous diabetic db/db mice and in vitro in sodium palmitate (PA)-stimulated and Abca1-SiRNA-transfected mouse tubular epithelial cells (mTECs). The results revealed that TSF treatment significantly ameliorated the renal injuries by lowering urinary albumin excretion and improving renal tissue injuries in diabetic (db/db) mice. Interestingly, the treatment with TSF also resulted in decreased cholesterol levels in the renal tissues of db/db mice, which was associated with increased expression of the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), the Liver X receptors (LXR), and ATP-binding cassette subfamily A member 1 (ABCA1), suggesting that TSF might attenuate diabetic kidney injury via a mechanism associated with improving cholesterol efflux in the diabetic kidney. This was investigated in vitro in mTECs, and the results showed that TSF reduced the PA-stimulated cholesterol accumulation in mTECs. Mechanistically, the addition of TSF was capable of reversing PA-induced downregulation of PGC-1α, LXR, and ABCA1 expression and cholesterol accumulation in mTECs, suggesting that TSF might act the protection via the PGC-1α-LXR-ABCA1 pathway to improve the cholesterol efflux in the renal tissues of db/db mice. This was further confirmed by silencing ABCA1 to block the promotive effect of TSF on cholesterol efflux in vitro. In conclusion, TSF might ameliorate diabetic kidney injuries by promoting ABCA1-mediated renal cholesterol efflux.
Highlights
Diabetic nephropathy (DN) is one of the major long-term microvascular complications of type 2 diabetes mellitus (T2DM) and is a leading cause of end-stage renal disease (ESRD) worldwide (Perco and Mayer, 2018)
Compared with db/m mice, serum levels of low-density lipid cholesterol (LDL-C), HDLC, total cholesterol (TC), and TG were significantly increased in db/db mice and were decreased in those treated with Tangshen Formula (TSF), the level of high-density lipid cholesterol (HDL-C) was not significantly affected by the treatment with TSF (Figure 1C)
Quantitative analysis revealed that cholesterol levels in the renal cortical tissues were highly increased in db/db mice compared with db/m mice, and TSF treatment decreased the renal cholesterol accumulation in db/db mice (Figure 2D)
Summary
Diabetic nephropathy (DN) is one of the major long-term microvascular complications of type 2 diabetes mellitus (T2DM) and is a leading cause of end-stage renal disease (ESRD) worldwide (Perco and Mayer, 2018). Hyperlipidemia, such as hypercholesterolemia, has been proposed as a risk factor for initiation and progression of DN (Kim et al, 2018). A recent study indicated that the increased ABCA1-mediated cholesterol efflux attenuated renal cholesterol accumulation in DN patients (Ganda et al, 2017)
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