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

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.

Notoginsenoside Fc ameliorates renal tubular injury and mitochondrial damage in acetaminophen-induced acute kidney injury partly by regulating SIRT3/SOD2 pathway.

Introduction: Mitochondria dysfunction is one of the primary causes of tubular injury in acute kidney injury (AKI). Notoginsenoside Fc (Fc), a new saponin isolated from Panax notoginseng, exhibited numerous pharmacological actions. However, the beneficial effects of Fc on renal tubular impairment and mitochondrial dysfunction in AKI have not been fully studied. Methods: In this study, we established acetaminophen (APAP)-induced AKI model in mice to examine the therapeutic impacts of Fc on AKI. Results: Our results showed that Fc could decrease the levels of the serum creatinine (Scr), blood urea nitrogen (BUN) and Cystatin C in mice with AKI. Fc also ameliorated renal histopathology, renal tubular cells apoptosis and restored expression of apoptosis-related proteins such as Bax, Bcl-2 and caspase3 (C-caspase3). Additionally, Fc increased the protein expression of SIRT3 and SOD2 in kidneys from mice with AKI. In vitro studies further showed Fc reduced the apoptosis of HK-2 cells exposure to APAP, attenuated the loss of mitochondrial membrane potential and decreased the formation of mitochondrial superoxide. Fc also partly restored the protein expression of Bax, Bcl-2, C-Caspase3, SIRT3, and SOD2 in HK-2 cells exposure to APAP. Conclusion: In summary, Fc might reduce renal tubular injury and mitochondrial dysfunction in AKI partly through the regulation of SIRT3/SOD2 pathway.

Astragaloside II Ameliorated Podocyte Injury and Mitochondrial Dysfunction in Streptozotocin-Induced Diabetic Rats.

Astragaloside II (AS II), a novel saponin purified from Astragalus membranes, has been reported to modulate the immune response, repair tissue injury, and prevent inflammatory response. However, the protective effects of AS II on podocyte injury in diabetic nephropathy (DN) have not been investigated yet. In this study, we aimed to investigate the beneficial effects of AS II on podocyte injury and mitochondrial dysfunction in DN. Diabetes was induced with streptozotocin (STZ) by intraperitoneal injection at 55 mg/kg in rats. Diabetic rats were randomly divided into four groups, namely, diabetic rats and diabetic rats treated with losartan (10 mg·kg-1·d-1) or AS II (3.2 and 6.4 mg·kg-1·d-1) for 9 weeks. Normal Sprague-Dawley rats were chosen as nondiabetic control group. Urinary albumin/creatinine ratio (ACR), biochemical parameters, renal histopathology and podocyte apoptosis, and morphological changes were evaluated. Expressions of mitochondrial dynamics-related and autophagy-related proteins, such as Mfn2, Fis1, P62, and LC3, as well as Nrf2, Keap1, PINK1, and Parkin, were examined by immunohistochemistry, western blot, and real-time PCR, respectively. Our results indicated that AS II ameliorated albuminuria, renal histopathology, and podocyte foot process effacement and podocyte apoptosis in diabetic rats. AS II also partially restored the renal expression of mitochondrial dynamics-related and autophagy-related proteins, including Mfn2, Fis1, P62, and LC3. AS II also increased the expression of PINK1 and Parkin associated with mitophagy in diabetic rats. Moreover, AS II facilitated antioxidative stress ability via increasing Nrf2 expression and decreasing Keap1 protein level. These results suggested that AS II ameliorated podocyte injury and mitochondrial dysfunction in diabetic rats partly through regulation of Nrf2 and PINK1 pathway. These important findings might provide an innovative therapeutic strategy for the treatment of DN.

Mechanism of progression of diabetic kidney disease mediated by podocyte mitochondrial injury.

Diabetic kidney disease (DKD) is an important diabetic microvascular complication, which has become the main cause of end-stage renal disease (ESRD) all over the world. It is of great significance to find effective therapeutic targets and improve the prognosis of the disease. Traditionally, it is believed that the activation of the renin-angiotensin-aldosterone system (RAAS) is the main reason for the progression of DKD, but with the progress of research, it is known that the production of proteinuria in patients with DKD is also related to podocyte injury and loss. Many studies have shown that mitochondrial dysfunction in podocytes plays an important role in the occurrence and development of DKD, and oxidative stress is also the main pathway and common hub of diabetes to the occurrence and development of microvascular and macrovascular complications. Thus, the occurrence and progression of DKD is correlated with not only the activation of the RAAS, but also the damage of mitochondria, oxidative stress, and inflammatory mediators. Besides, diabetes-related metabolic disorders can also cause abnormalities in mitochondrial dynamics, autophagy and cellular signal transduction, which are intertwined in a complex way. Therefore, in this review, we mainly explore the mechanism and the latest research progress of podocyte mitochondria in DKD and summarize the main signal pathways involved in them. Thus, it provides feasible clinical application and future research suggestions for the prevention and treatment of DKD, which has important practical significance for the later treatment of patients with DKD.