Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.

NLRP3/IL-1β activation via thioredoxin (TRX)/thioredoxin-interacting protein (TXNIP) following mitochondria ROS (mtROS) overproduction plays a key role in inflammation. However, the involvement of this process in tubular damage in the kidneys of patients with diabetic nephropathy (DN) is unclear. Here, we demonstrated that mtROS overproduction is accompanied by decreases in TRX expression and TXNIP up-regulation. In addition, we discovered that mtROS overproduction is also associated with increases in NLRP3/IL-1β and TGF-β expression in the kidneys of patients with DN and db/db mice. We reversed these changes in db/db mice by administering a peritoneal injection of MitoQ, an antioxidant targeting mtROS. Similar results were observed in human tubular HK-2 cells subjected to high-glucose (HG) conditions and treated with MitoQ. Treating HK-2 cells with MitoQ suppressed the dissociation of TRX from TXNIP and subsequently blocked the interaction between TXNIP and NLRP3, leading to the inhibition of NLRP3 inflammasome activation and IL-1β maturation. The effects of MitoQ were enhanced by pretreatment with TXNIP siRNA and abolished by pretreatment with monosodium urate (MSU) and TRX siRNA in vitro. These results suggest that mitochondrial ROS-TXNIP/NLRP3/IL-1β axis activation is responsible for tubular oxidative injury, which can be ameliorated by MitoQ via the inhibition of mtROS overproduction.

Mohite-type ternary sulfide Cu2SnS3, which has been intensively studied in the photovoltaic field, has recently attracted much attention as an outstanding p-type eco-friendly thermoelectric material.

Diabetic Nephropathy (DN) is believed to be a major microvascular complication of diabetes. The hallmark of DN includes deposition of Extracellular Matrix (ECM) proteins, such as, collagen, laminin and fibronectin in the mesangium and renal tubulo-interstitium of the glomerulus and basement membranes. Such an increased expression of ECM leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis. The characteristic morphologic glomerular mesangial lesion has been described as Kimmelstiel–Wilson nodule, and the process at times is referred to as diabetic nodular glomerulosclerosis. Thus, the accumulation of ECM proteins plays a critical role in the development of DN. The relevant mechanism(s) involved in the increased ECM expression and their regulation in the kidney in diabetic state has been extensively investigated and documented in the literature. Nevertheless, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules including, Notch, Wnt, mTOR, TLRs and small GTPase may play a pivotal role in the modulation of ECM regulation and expression in DN. Such modulation could be operational for instance Notch though Notch1/Jagged1 signaling, Wnt by Wnt/β-catenin pathway and mTOR via PI3-K/Akt/mTOR signaling pathways. All these pathways may be critical in the modulation of ECM expression and tubulo-interstitial fibrosis. In addition, TLRs, mainly the TLR2 and TLR4, by TLR2-dependent and TGF-β-dependent conduits, may modulate ECM expression and generate a fibrogenic response. Small GTPase like Rho, Ras and Rab family by targeting relevant genes may also influence the accumulation of ECM proteins and renal fibrosis in hyperglycemic states. This review summarizes the recent information about the role and mechanisms by which these molecules and signaling pathways regulate ECM synthesis and its expression in high glucose ambience in vitro and in vivo states. The understanding of such signaling pathways and the molecules that influence expression, secretion and amassing of ECM may aid in developing strategies for the amelioration of diabetic nephropathy.