Formononetin Attenuates Renal Tubular Injury and Mitochondrial Damage in Diabetic Nephropathy Partly via Regulating Sirt1/PGC-1α Pathway

Abstract

Mitochondrial abnormality is one of the main factors of tubular injury in diabetic nephropathy (DN). Formononetin (FMN), a novel isoflavonoid isolated from Astragalus membranaceus, has diverse pharmacological activities. However, the beneficial effects of FMN on renal tubular impairment and mitochondrial dysfunction in DN have yet to be studied. In this study, we performed in vivo tests in Streptozotocin (STZ) -induced diabetic rats to explore the therapeutic effects of FMN on DN. We demonstrated that FMN could ameliorate albuminuria and renal histopathology. FMN attenuated renal tubular cells apoptosis, mitochondrial fragmentation and restored expression of mitochondrial dynamics-associated proteins, such as Drp1, Fis1 and Mfn2, as well as apoptosis-related proteins, such as Bax, Bcl-2 and cleaved-caspase-3. Moreover, FMN upregulated the protein expression of Sirt1 and PGC-1α in diabetic kidneys. In vitro studies further demonstrated that FMN could inhibit high glucose-induced apoptosis of HK-2 cells. FMN also reduced the production of mitochondrial superoxide and alleviated mitochondrial membrane potential (MMP) loss. Furthermore, FMN partially restored the protein expression of Drp1, Fis1 and Mfn2, Bax, Bcl-2, cleaved-caspase-3, Sirt1 and PGC-1α in HK-2 cells exposure to high glucose. In conclusion, FMN could attenuate renal tubular injury and mitochondrial damage in DN partly by regulating Sirt1/PGC-1α pathway.

The efficacy and potential mechanism of Danggui Buxue Decoction in treating diabetic nephropathy: A meta-analysis and network pharmacology

“…[ 30 ] Formononetin further develops albuminuria and renal histopathology and weakens renal cylindrical injury and mitochondrial harm in DN by regulating the Sirt1/PGC-1α pathway. [ 31 ] Quercetin, with anti-inflammatory and antioxidant effects, can be metabolized into glucuronides, sulfates, and methyl conjugates. [ 32 ] Isorhamnetin is not only used to prevent cardiovascular diseases but also has good pharmacological effects on anti-tumor, anti-bacterial, and anti-proliferative aspects.…”

Natural products for kidney disease treatment: Focus on targeting mitochondrial dysfunction

“…Formononetin can alleviate nephrotoxicity in methotrexate-, cisplatin-and gentamicin-induced kidney injury and DKD (Aladaileh et al, 2019;Oza and Kulkarni, 2019;Hao et al, 2021;Althunibat et al, 2022). Formononetin promotes mitochondrial biogenesis via Sirtuin-1-PGC-1α pathway, which plays an important role in kidney protection (Rasbach and Schnellmann, 2008;Huang et al, 2022e). Formononetin treatment could attenuate tubular cell apoptosis and podocyte injury, then further to decrease Frontiers in Pharmacology frontiersin.org urinary albumin excretion and ameliorate the progression of DKD (Huang et al, 2022e).…”

“…Formononetin promotes mitochondrial biogenesis via Sirtuin-1-PGC-1α pathway, which plays an important role in kidney protection (Rasbach and Schnellmann, 2008;Huang et al, 2022e). Formononetin treatment could attenuate tubular cell apoptosis and podocyte injury, then further to decrease Frontiers in Pharmacology frontiersin.org urinary albumin excretion and ameliorate the progression of DKD (Huang et al, 2022e).…”

The role of Mitochondrial Fission Proteins in Mitochondrial Dynamics in Kidney Disease

“…Mitochondrial fragmentation is an important pathogenic feature of renal tubular cell injury, and FIS1 and DRP1 play an important role in mitochondrial fission. In renal tubular cells with DKD, mitochondria are fragmented and FIS1 is increasing, while downregulation of FIS1 can improve mitochondrial morphology and reduce apoptosis of renal cells [ 149 , 150 ]. It has been shown that pharmacological inhibition of DRP1 expression and protection of mitochondria from excessive division can effectively stop progression of DKD [ 99 ].…”

“…Polydatin (PD) is a resveratrol glycoside that protects kidney function in patients with diabetic nephropathy, and PD is able to inhibit podocyte injury by suppressing DRP1 expression and mitochondrial fragmentation [ 159 ]. Formononetin (FMN) is a novel isoflavonoid constituent isolated from Astragalus membranaceus; it can reduce mitochondrial fission protein, increase mitochondrial fusion protein, and improve mitochondrial damage in diabetic nephropathy [ 150 ]. P110 is an inhibitor of DRP1 and FIS1 interaction and can improve mitochondrial damage by blocking the interaction between the two fissions [ 160 ].…”