BaoShenTongLuo formula protects against podocyte injury by regulating AMPK-mediated mitochondrial biogenesis in diabetic kidney disease

Abstract

Background Mitochondrial dysfunction is considered to be an important contributor in podocyte injury under diabetic conditions. The BaoShenTongLuo (BSTL) formula has been shown to reduce podocyte damage and postpone the progression of diabetic kidney disease (DKD). The potential mechanisms underlying the effects of BSTL, however, have yet to be elucidated. In this study, we aimed to investigate whether the effects of BSTL are related to the regulation of mitochondrial biogenesis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. Methods High-Performance Liquid Chromatography Electrospray Ionization Mass Spectrometer (HPLC–ESI–MS) analysis was performed to investigate the characteristics of pure compounds in BSTL. db/db mice and mouse podocyte clone-5 (MPC5) cells were exposed to high glucose (HG) to induce DKD and podocyte damage. Body weight, random blood glucose, urinary albumin/creatinine ratio (UACR), indicators of renal function and renal histological lesions were measured. Markers of podocyte injury, mitochondrial morphology, mitochondrial deoxyribonucleic acid (mtDNA) content, mitochondrial respiratory chain complexes activities, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) levels were assessed. Protein expressions of AMPK, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), transcription factor A (TFAM), mitochondrial fusion protein 2 (MFN2) and dynamin-related protein 1 (DRP1) were also detected. MPC5 cells were transfected with AMPKα small interfering RNA (AMPKα siRNA) to determine the underlying mechanisms of BSTL improvement of mitochondrial function under diabetic conditions. Results In vivo, treatment with BSTL reduced the UACR levels, reversed the histopathological changes in renal tissues, and alleviated the podocyte injury observed in db/db mice. After BSTL treatment, the decreased mtDNA content and mitochondrial respiratory chain complex I, III, and IV activities were significantly improved, and these effects were accompanied by maintenance of the protein expression of p-AMPKαT172, PGC-1α, TFAM and MFN2. The in vitro experiments also showed that BSTL reduced podocyte apoptosis, suppressed excessive cellular ROS production, and reversed the decreased in MMP that were observed under HG conditions. More importantly, the effects of BSTL in enhancing mitochondrial biogenesis and reducing podocyte apoptosis were inhibited in AMPKα siRNA-treated podocytes. Conclusion BSTL plays a crucial role in protecting against podocyte injury by regulating the AMPK-mediated mitochondrial biogenesis in DKD.

Roles of Mitochondrial Dysfunction in Diabetic Kidney Disease: New Perspectives from Mechanism to Therapy

“…A reduction in PGC-1α, an important factor involved in mitochondrial biogenesis, has been shown to promote DKD. AMPK is a key link in the regulation of cellular metabolism, and it can directly increase the level of PGC-1α expression to promote mitochondrial biogenesis and thus slow down the progression of DKD [ 37 ]. The pathway is also known as the histone pathway.…”

“…In the mitochondrial biogenesis link, AMPK, as an important molecule in the positive regulation of biogenesis, can activate PGC-1α downstream and also regulate Mfn2 to ameliorate oxidative stress. After the administration of BSTL in db/db mice, the phosphorylation of AMPK in podocytes was restored and proteinuria appeared to be correspondingly reduced [ 37 ]. Also, in the development of renal tubulointerstitial fibrosis, Schisandrin B reduces the progression of tubular fibrosis by binding to the AMPKSer172 phosphorylation site [ 86 ].…”

“Qi Nan” agarwood restores podocyte autophagy in diabetic kidney disease by targeting EGFR signaling pathway

“…Podocytes serve as the primary constituent of the glomerular filtration barrier structure [4,5]. Podocyte damage, apoptosis, and shedding are important causes of continued albuminuria, contributing to the relentless aggravation of DKD [6]. It should be emphasized that podocytes are highly specific, terminally differentiated visceral epithelial cells that have little ability to proliferate and repair once damaged and lost.…”