Single-cell transcriptome atlas in C57BL/6 mice encodes morphological phenotypes in the aging kidneys.

C57BL/6 mice are frequently utilized as murine models with the desired genetic background for altertion in multiple research contexts. So far, there is still a lack of comprehensive kidney morphology and single-cell transcriptome atlas at all stages of growth of C57BL/6 mice. To provide an interactive set of reference standards for the scientific community, we performed the current study to investigate the kidney's development throughout the capillary-loop stage until senescence. Eight groups, with five to six mice each, represented embryonic stage (embryos 18.5 days), suckling period (1 day after birth), juvenile stage (1 month old), adulthood (containing 3 months old, 6 months old and 10 months old), reproductive senescence stage (20 months old), and post-senescence stage (30 months old), respectively. With age, the thickness of the glomerular basement membrane (GBM) was increased. Notably, GBM knobs appeared at three months and became frequent with age. Using single-cell transcriptome data, we evaluated how various biological process appear in particular cell types and investigated the potential mechanism of formation of GBM konbs. In conclusion, having access to detailed kidney morphology and single-cell transcriptome maps from C57BL/6 mice at various developmental stages of C57BL/6 mice would be a novel and major resource for biological research and testing of prospective therapeutic approaches.

Nogo-B Promotes Endoplasmic Reticulum Stress-Mediated Autophagy in Endothelial Cells of Diabetic Nephropathy.

Aims: Endothelial cells are the critical targets of injury in diabetic nephropathy (DN), and endothelial cell lesions contribute to the disease progression. Neurite outgrowth inhibitor B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, plays a pivotal role in vascular remodeling after injury, and maintains the structure and function of the ER. Yet, the role of Nogo-B in the regulation of ER stress and endothelial cell injury remains largely unknown. Herein, we tested the hypothesis that Nogo-B activates ER stress-mediated autophagy and protects endothelial cells in DN. Results: The level of Nogo-B was decreased in glomerular endothelial cells in biopsy specimens from DN patients. In vivo and in vitro studies have shown that silencing Nogo-B activated ER stress signaling, and affected the expression of autophagy-related marker early growth response 1 and microtubule-associated protein light chain 3 (LC3) in endothelial cells in hyperglycemic condition. Conclusion and Innovation: These results denote that Nogo-B contributes to ER stress-mediated autophagy and protects endothelial cells in DN, providing new evidence for understanding the role of ER stress-mediated autophagy in endothelial cells of DN.

LINC00355 Mediates CTNNBIP1 Promoter Methylation and Promotes Endoplasmic Reticulum Stress-Induced Podocyte Injury in Diabetic Nephropathy.

Aims: Endoplasmic reticulum stress (ER stress) plays an important role in podocyte injury in diabetic nephropathy. Wnt/ß-catenin signaling modulates ER stress, yet the epigenetic regulation of ß-catenin in ER stress and podocyte injury remains largely unknown. Herein, we tested the hypothesis that LINC00355 recruits EZH1 to the promoter region of CTNNBIP1 and trimethylates H3K4 to regulate ER-stress induced podocyte injury in DN. Results: LINC00355 is upregulated in podocytes and correlates with renal function decline in DN patients. LINC00355 localizes in the nucleus and exerts biological functions by directly binding EZH1, which epigenetically targets CTNNBIP1 through repressive trimethylation of H3K4 and activates Wnt/ß-catenin signaling and ER stress. Further, we provide mechanistic evidences that LINC00355 recruits EZH1 to the promoter region of CTNNBIP1 and regulates ER-stress induced podocyte injury in DN. Innovation and Conclusion: Our data reveal a major role of LINC00355/EZH1/CTNNBIP1 network in triggering podocyte injury, providing new evidences for understanding the role of ER stress in DN. Antioxid. Redox Signal. 39, 225-240.

Protective mechanism of 1-methylhydantoin against lung injury induced by paraquat poisoning.

Paraquat (PQ), one of the most widely used herbicides worldwide, causes severe toxic effects in humans and animals. 1-methylhydantoin (MH) is an active ingredient of Ranae Oviductus, which has broad pharmacological activities, e.g., eliminating reactive oxygen species and inhibiting inflammation. This study investigated the effects of MH on lung injury induced by PQ. A PQ poisoning model was established by intragastric infusion of PQ (25 mg/kg), and the control group was simultaneously gavaged with the same dose of saline. The MH group was intraperitoneally injected with 100 mg/kg once per day after intragastric infusion of PQ (25 mg/kg) for five consecutive days. All animals were sacrificed on the sixth day, and the lung tissues were dissected for metabolomics analysis. The lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, TNF-α and malondialdehyde (MDA) content were determined according to the instructions of the detection kit. Compared with that in the control group, the content of LDH, TNF-α and MDA in the lung tissue of the PQ group was significantly higher, and the activity of SOD in the lung tissue was significantly lower (all p<0.05). Compared with that in the control group, the content of LDH, TNF-α and MDA in the MH group was significantly higher, and the activity of SOD was significantly lower (all p<0.05). However, the differences in SOD activity, LDH activity between the PQ and MH groups were not statistically significant (all p > 0.05). There were significant differences in MDA and TNF-α content between the PQ group and MH group (all p<0.05). MH decreased the production of malondialdehyde and TNF-α to protect against the lung injury caused by PQ poisoning, but it had no significant effect on the activity of LDH and SOD. There were significant differences in metabolomics between the MH group and the PQ poisoning group, primarily in bile acid biosynthesis and metabolism of cholesterol, nicotinate, nicotinamide, alanine, aspartate, glutamate, glycine, threonine, serine, phenylalanine and histidine. Therefore, this study highlights that MH has non-invasive mechanisms and may be a promising tool to treat lung injury induced by PQ poisoning.