Alleviation by Mahuang Fuzi and Shenzhuo Decoction in High Glucose-Induced Podocyte Injury by Inhibiting the Activation of Wnt/β-Catenin Signaling Pathway, Resulting in Activation of Podocyte Autophagy

Abstract

Background. Organ fibrosis is a common endpoint of a variety of diseases. Many studies have shown that the pathogenesis of diabetic kidney disease (DKD) is related to the excessive activation of the Wnt/β-catenin signaling pathway on podocytes, so the treatment of DKD starts from this signaling pathway. At the same time, DKD, as a metabolic disease, has many connections related to podocyte autophagy. Objectives. We experimented the effects of Mahuang Fuzi and Shenzhuo decoction (MFSD) which is the combination of Mahuang Fuzi decoction and Shenzhuo decoction in traditional Chinese medicine compounds used “The Golden Chamber” in high glucose-induced podocytes, determined whether this effect was related to Wnt/β-catenin signaling pathway, and further investigated the relationship between this effect and autophagy. Methods. The mice podocytes were stimulated by using 30 mmol/L of high glucose and serum containing MFSD or Wnt/β-catenin signaling pathway inhibitor DKK1 (100 ng/ml) was used to intervene podocytes before high glucose stimulation. Podocyte injury-related proteins, Wnt/β-catenin signaling pathway-related proteins, and autophagy-related proteins were detected by using western blotting and immunofluorescence analysis. Results. Our results showed that DKK1 and MFSD treatment significantly upregulated the protein expressions of nephrin, podocin, podocalyxin, and podoplanin in high glucose-induced podocytes and downregulated the β-catenin protein expression. Furthermore, the protein expressions of beclin1, LC3B, and P62 were also significantly increased in high glucose-induced podocytes. Conclusion. Our experiments confirmed that the destruction of podocytes in DKD is related to the excessive activation of Wnt/β-catenin signaling pathway and the inhibition of autophagy after activation. MFSD treatment can inhibit the activation of Wnt/β-catenin signaling pathway in podocytes stimulated by high glucose and helpful in reducing the podocyte injury. This protective mechanism can be related to the enhancement of podocyte autophagy by MFSD treatment.

The Wnt Signaling Pathway in Diabetic Nephropathy

“…Recent studies have shown that podocyte injury is an early and critical stage of the progression of DN ( Zhang et al, 2015 ). After receiving harmful stimuli, such as high glucose ( Dai et al, 2020 ; Li and Siragy, 2014 ) or genetic mutation ( Bork et al, 2020 ), the podocyte is known to respond differently according to the severity and duration of the injury. Previous studies have shown that podocyte tend to undergo hypertrophy or autophagy in the process of DN and that this occurs via the mTOR signaling pathway ( Bork et al, 2020 ).…”

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

“…Clinical trials and experimental studies have shown that CHMs have great advantages in reducing proteinuria and improving renal function, by focusing on the anti-inflammatory, anti-oxidative, antiapoptotic and anti-fibrotic effects (Chen et al, 2019a;Miao et al, 2020;Wang et al, 2020b;Wang et al, 2021a;Wang et al, 2021b). In addition, CHMs play a vital role in alleviating renal fibrosis by regulating the Wnt/β-catenin signaling pathway (Liu et al, 2019;Dai et al, 2020).…”

The Ameliorative Effect of Mahuang Fuzi and Shenzhuo Decoction on Membranous Nephropathy of Rodent Model is Associated With Autophagy and Wnt/β-Catenin Pathway

“…These ingredients have been reported in the literature for kidney disease treatment ( Tan et al, 2014 ; Liu et al, 2019 ; Dai et al, 2020 ). MFSD activates podocyte autophagy by inhibiting activation of the Wnt/β-catenin signaling pathway and alleviates hyperglycemia-induced podocyte injury ( Dai et al, 2020 ). According to the TCM theory, MFSD can treat MN through warming yang and resolving exterior methods.…”

“…Mahuang Fuzi and Shenzhuo Decoction (MFSD), as a classic prescription in Treatise on Febrile Diseases used clinically for 1800 years, consists of 6 kinds of Chinese herbs, namely ephedra, aconite, dried ginger, poria cotta, atractylodes, and licorice. These ingredients have been reported in the literature for kidney disease treatment ( Tan et al, 2014 ; Liu et al, 2019 ; Dai et al, 2020 ). MFSD activates podocyte autophagy by inhibiting activation of the Wnt/β-catenin signaling pathway and alleviates hyperglycemia-induced podocyte injury ( Dai et al, 2020 ).…”