Renal protective effect and mechanism research of hypoxia inducible factor-1α inhibitor YC-1 in diabetic nephropathy mice

Objective·To investigate the effect of hypoxia inducible factor-1α (HIF-1α) inhibitor YC-1 on the progression of diabetic nephropathy (DN) in mice and the potential mechanism.Methods·Ten-week-old male db/db mice (DN model) and their nondiabetic wild-type (WT) littermates were divided into 4 groups (n=6) according to whether treated with YC-1 or not: WT group, WT+YC-1 group, DB group, and DB+YC-1 group. The treatment groups were intraperitoneally injected with YC-1 (20 mg·kg-1) once a day, while the non-treatment groups received the same volumes of DMSO injection. After a total of 8 weeks of intervention, blood glucose, body weight, and kidney weight of all mice were measured. Serum, urine and kidney tissue samples were harvested. Serum creatinine, urinary albumin-to-creatinine ratio (UACR), and urine neutropil gelatinase-associated lipocalin (NGAL) levels were detected. The kidneys were stained with ‎hemat‎oxyli‎n-eosin (H-E) and periodic acid-Schiff (PAS) to observe the pathological changes. Masson staining was used to detect fibrosis, collagen-Ⅰ was detected by immunohistochemistry, and α-smooth muscle actin (α-SMA) was detected by Western blotting. The expression of HIF-1α was detected by both Western blotting and immunohistochemistry. TUNEL staining and Western blotting for apoptosis-related proteins were used to observe the cell apoptosis level. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were detected by the kits. Endoplasmic reticulum stress (ERS) markers, including immunoglobulin heavy chain binding protein (BiP, also known as GRP78), phospho-protein kinase R-like endoplasmic reticulum kinase (p-PERK), total PERK, phospho-eukaryotic initiation factor 2α (p-eIF2α), total eIF2α, activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were determined by Western blotting.Results·Compared with the WT group, the DB group showed significant rise of blood glucose, loss of renal function, severe kidney histopathology injuries and kidney fibrosis, increase of renal HIF-1α expression, and aggravated oxidative stress and ERS. Whilst there were no significant changes in blood glucose, YC-1 treatment notably reduced kidney weight/body weight ratio, serum creatinine, UACR, and urine NGAL levels in db/db mice. YC-1 treatment ameliorated kidney histopathology injuries and kidney fibrosis, and decreased the expressions of collagen-Ⅰ and α-SMA. YC-1 treatment also reduced the number of TUNEL positive cells, the expression of HIF-1α and pro-apoptotic proteins including BAX and cleaved caspase-3, and MDA level in the kidneys of db/db mice, while promoting anti-apoptotic protein BCL-2 expression and SOD activity. The expressions of ERS markers GRP78, p-PERK, p-eIF2α, ATF4, and CHOP were likewise significantly decreased in DB+YC-1 group.Conclusion·HIF-1α inhibitor YC-1 inhibits oxidative stress and abnormal activation of ERS, improving cell apoptosis and fibrosis in the kidneys of DN mice, which would attenuate the aggravation of pathological damage and loss of kidney function

Tectonomagmatic Setting and Cu-Ni Mineralization Potential of the Gayahedonggou Complex, Northern Qinghai–Tibetan Plateau, China

The Gayahedonggou magmatic Cu-Ni sulfide deposit was recently discovered in the East Kunlun orogenic belt (Northern Tibetan Plateau, China). The mineralization in this region is associated with mafic–ultramafic intrusions. To date, the formation age and metallogenic model of these ore-bearing intrusions have not been studied systematically. In this paper, the petrology, zircon U-Pb chronology, and geochemistry of ore-bearing wehrlite and quartz diorite are investigated. The results show that the zircon U-Pb isotopic age of wehrlite is 419.9 ± 1.5 Ma with an average εHf(t) value of 3.0, indicating that wehrlite originated from a depleted mantle or the asthenosphere. The (La/Yb)N, (La/Sm)N, (Gd/Yb)N, Nb/U, and Ce/Pb ratios of wehrlite are between 3.01–7.14, 1.69–3.91, 1.36–1.51, 2.07–2.93, and 0.55–1.42, respectively, indicating that the parent magma of the wehrlite had been contaminated by the upper crust. The zircon U-Pb isotopic age of quartz diorite is 410.2 ± 3.5 Ma with an average εHf(t) value of 8.0, and the A/CNK and A/NK ratio of quartz diorites ranges from 1.02 to 1.04 and from 2.13 to 2.23, respectively. These features are similar to those of the type I granite, and the quartz diorite was likely derived from the lower crust. Combined with the regional geological evolution, the Gayahedonggou complex formed in a post-collision extensional environment. The pyroxene in the Gayahedonggou complex is mainly clinopyroxene, which is enriched in the CaO content, indicating that the CaO content of the parent magma of the Gayahedonggou complex is high or that the complex has been contaminated by Ca-rich surrounding rocks, which hinders Cu-Ni mineralization

Petrogenesis of Middle Triassic Adakite-like Intrusions in the Asiha Orogenic Gold Deposit, East Kunlun Orogenic Belt, China

The East Kunlun Orogenic Belt is considered as one of the important gold mineralization regions in the Tethys tectonic domain. These orogenic gold deposits are related to intermediate-acid intrusions formed at the end of Paleo-Tethys evolution, but the petrogenesis is controversial. This paper presents a new study on the geochemistry of zircon U-Pb, O, S, and Pb isotopic compositions of Asiha quartz diorite, granite porphyry, and sulfides. The geochemical features of quartz diorite and granite porphyry are consistent with the modern adakite, with high content of Sr but low content of Y, Yb, and MgO. Magmatic zircons from these two types of intrusion yielded U-Pb ages of 238.4 ± 1.4 Ma and 240 ± 1.7 Ma, respectively. The high O isotopic composition of Asiha complex may reflect that crust or crustal derivates were incorporated into the magmatic melt, and the Pb isotope characteristics indicates a lower crust origin. The δ34S values of pyrites range from 4.9‰ to 11.6‰. This study infers that the Asiha complex perhaps formed by partial melting of the Paleo-Tethys subducted oceanic crust with seafloor sediments and is markedly different from the traditional adakite. Asiha deposit is an orogenic gold deposit related to adakite-like rocks, which formed in Triassic in the East Kunlun Orogenic Belt