Tangshen Formula Attenuates Diabetic Nephropathy by Promoting ABCA1-Mediated Renal Cholesterol Efflux in db/db Mice

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.

Protective Role of Tangshen Formula on the Progression of Renal Damage indb/dbMice by TRPC6/Talin1 Pathway in Podocytes

“…The typical pathologic damage changes in db/db mice, including glomerular hypertrophy, mesangial expansion, thickened GBM, and abnormal deposition of fibronectin, collagen type IV, and collagen type I, were relieved by TSF or irbesartan treatment (Figures 1(e) , 1(f) , and S2 ). Therefore, TSF could effectively alleviate proteinuria and renal injury in db/db mice, which is consistent with our previously reported results [ 29 , 40 ].…”

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…The anti-lipotoxic effect of curcumin, berberine, oligonol-derived lychee fruit, and oryzanol-derived rice bran oil has also been demonstrated due to their capacity to reduce inflammatory, oxidative stress, and mitochondrial dysfunction markers in diabetic murine models [201][202][203][204][205]. Tangshen formula, a traditional Chinese formulation, was able to alleviate abnormal renal lipid accumulation and kidney damage in db/db mice by promoting ABCA1-mediated efflux cholesterol [206]. Thymol, a monoterpene phenolic compound found mainly in oil of thyme (an herb known as Thymus vulgaris) and Omacor (n-3 polyunsaturated fatty acids), decreased renal lipid accumulation through the modulation of SREBP-1-mediated lipogenic pathway [207,208].…”

Tangshen Formula Alleviates Hepatic Steatosis by Inducing Autophagy Through the AMPK/SIRT1 Pathway

“…In our preliminary multicenter, randomized, double-blind, and placebo-controlled trial, TSF significantly reduced proteinuria, improved the estimated glomerular filtration rate (eGFR) among patients with DKD, and exhibited a beneficial effect in improving plasma lipid metabolism (Yu et al, 2011; Li et al, 2015). Additional studies from our group also found that TSF not only exerted a renal protective effect in decreasing urinary albumin excretion rate and glomerulosclerosis but also improved lipid metabolism in spontaneous DKD rodents, including Otsuka Long-Evans Tokushima Fatty rats and db/db mice (Zhang et al, 2011; Kong et al, 2016; Liu et al, 2018). However, little is known about the effect and potential mechanism of TSF on hepatic steatosis.…”