Berberine Protects Glomerular Podocytes via Inhibiting Drp1-Mediated Mitochondrial Fission and Dysfunction

Abstract

Elevated levels of plasma free fatty acid (FFA) and disturbed mitochondrial dynamics play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, the mechanisms by which FFA leads to mitochondrial damage in glomerular podocytes of DKD and the effects of Berberine (BBR) on podocytes are not fully understood. Methods : Using the db/db diabetic mice model and cultured mouse podocytes, we investigated the molecular mechanism of FFA-induced disturbance of mitochondrial dynamics in podocytes and testified the effects of BBR on regulating mitochondrial dysfunction, podocyte apoptosis and glomerulopathy in the progression of DKD. Results : Intragastric administration of BBR for 8 weeks in db/db mice significantly reversed glucose and lipid metabolism disorders, podocyte damage, basement membrane thickening, mesangial expansion and glomerulosclerosis. BBR strongly inhibited podocyte apoptosis, increased reactive oxygen species (ROS) generation, mitochondrial fragmentation and dysfunction both in vivo and in vitro . Mechanistically, BBR could stabilize mitochondrial morphology in podocytes via abolishing palmitic acid (PA)-induced activation of dynamin-related protein 1 (Drp1). Conclusions : Our study demonstrated for the first time that BBR may have a previously unrecognized role in protecting glomerulus and podocytes via positively regulating Drp1-mediated mitochondrial dynamics. It might serve as a novel therapeutic drug for the treatment of DKD.

Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3‐dependent mitochondrial homeostasis through SDF‐1α/CXCR4 pathway

“…In our experiment, altered mitochondrial dynamics‐associated proteins and increased fragmented mitochondria were both observed in STZ‐induced diabetic mouse tubules and in albumin‐treated cultured tubular cells, showing that the increased expression of mitochondrial fission protein Drp1, but the decreased Mfn2 and OPA1 level in mitochondrial fusion process. Considering Drp1 activation involves posttranslational modifications, and the phosphorylation of Drp1 plays a role in mitochondrial fission process, 46,47 In this context, we also found that phosphorylation of Drp1 at ser616 site was increased under diabetic condition both in vitro and in vivo. These fusion and fission events together indicated impaired mitochondrial dynamics process homeostasis, which would inevitably lead to excessive ROS generation, initiate the mitochondrial apoptotic cascade, and consequently induce cell apoptosis.…”

Berberine protects against diabetic kidney disease via promoting PGC‐1α‐regulated mitochondrial energy homeostasis

“…The db/db mice were used as DKD models (Sharma, McCue, & Dunn, 2003) and randomly separated into three groups: db/db + vehicle, db/db + 200 mg·kg −1 ·day −1 of berberine (BBRL), and db/db + 300 mg·kg −1 ·day −1 of berberine (BBRH), with 10 mice per group. The dose of berberine was based on our previous animal studies and other research (Dong et al, 2016; Qin et al, 2019; Zhou & Zhou, 2010). Intragastric administration of berberine or vehicle was started at 7 weeks of age and maintained for 8 weeks.…”

“…The antibody‐based procedures used in this study comply with the recommendations made by the British Journal of Pharmacology (Alexander et al, 2018). Western blotting was conducted as described previously (Qin et al, 2019). Antibodies used were as follows: AMPK (Cell Signaling Technology, Cat# 4811, RRID: AB_11178532), p‐AMPK (Cell Signaling Technology, Cat# 2535, RRID: AB_331250), PGC‐1α (Santa Cruz Biotechnology, Cat# sc‐518025, RRID: AB_2755043), carnitine palmitoyltransferase 1 (CPT1; Cell Signaling Technology, Cat# 12252, RRID: AB_2797857), acetyl‐CoA carboxylase (ACC) Cell Signaling Technology, Cat# 3676, RRID: AB_2219397), phosphorylate ACC (Cell Signaling Technology, Cat# 11818, RRID: AB_2687505), cluster of differentiation 36 (CD36; Novus, Cat# NB400‐144, RRID: AB_10003498), β‐actin (Cell Signaling Technology Cat# 4970, RRID: AB_2223172), anti‐rabbit secondary antibody (Cell Signaling Technology, Cat# 5151, RRID: AB_10697505), and anti‐mouse secondary antibody (Cell Signaling Technology, Cat# 5257, RRID: AB_10693543).…”

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…Resveratrol and anthocyanin-rich Seoritae extract prevents lipotoxic and glucotoxic effects through AMPK-PGC-1α axis in db/db mice [199,200]. 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].…”