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The expression of Numb was upregulated in both ischemia-reperfusion- and cisplatin-induced AKI. Depletion of Numb from proximal tubules (PT-Nb-KO) exacerbated AKI shown as more severe renal tubular damage and higher serum creatinine than wild-type mice. Numb depletion alone significantly increased mitochondrial fragmentation without altering mitochondrial mass and function, including adenosine triphosphate production, mitochondrial membrane potential, oxygen consumption, and reactive oxygen species production. However, mitochondrial fragmentation and dysfunction were significantly aggravated after cisplatin exposure in PT-Nb-KO mice. Mechanistically, Numb depletion triggered dynamin-related protein 1 (Drp1) recruitment to mitochondria by increasing the phosphorylation of Drp1 at serine 656 residue (human Drp1 ser). Inhibiting the activity of Rho-associated coiled-coil containing protein kinase (ROCK) by Y-27632 attenuated phosphorylation of Drp1 ser and mitochondrial fragmentation in Numb-deficient cells. Administration of mdivi-1, a pharmacological inhibitor of Drp1, restored mitochondrial morphology, attenuated cisplatin-induced tubular injury, and renal dysfunction in PT-Nb-KO mice. Innovation and Conclusion: Our data suggest that Numb depletion promotes mitochondrial fragmentation by promoting the phosphorylation of Drp1 Ser and thus exacerbates cisplatin-induced mitochondrial dysfunction and tubular cell apoptosis. These findings add a novel insight into modulating mechanism of mitochondrial dynamics during AKI. Antioxid. Redox Signal. 00, 000-000.

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The chemical binding between metal compounds and polysulfides provides a good solution to inhibit shuttle effect in Li‐S batteries. However, the Sabatier principle predicts that overly strong adsorption will commonly hinder the conversion of polysulfides, so building the synergetic effect mechanism between “strong adsorption” and “fast conversion” for polysulfides is a significant strategy. To realize this goal, in this study, the defect‐enriched Co9S8 hollow prisms (DHCPs) as both S host and catalyst material for Li‐S batteries are designed. Based on in situ UV–vis spectroscopy results, it is found that DHCPs can profitably promote the generation of S3·−${\rm{S}}_3^{\cdot{\bm{ - }}}$ radicals during the discharge process. In the case of the relatively high conversion barrier of “liquid–liquid” reaction, the generated S3·−${\rm{S}}_3^{\cdot{\bm{ - }}}$ radicals are responsible for the fast conversion reaction via a unique reaction pathway. When the sulfur loading is 4.63 mg cm−2, the cell with DHCP/S cathode delivers a high areal capacity of 4.75 mAh cm−2 at 0.1 C and keeps a high capacity of 2.99 mAh cm−2 after 100 cycles at 0.5 C. This study provides a positive attempt to achieve “strong adsorption” and “fast conversion” of polysulfides simultaneously, which will convincingly boost the development and practical process of Li‐S batteries.

Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury with various origins. HLA-DQA1, -DQB1, and -DRB1 have been associated with development of tubulointerstitial nephritis and uveitis (TINU) syndrome in case reports and small case series, but information about HLA genetic susceptibility to drug hypersensitivity–related ATIN (D-ATIN) or other types of ATIN is limited. In this article, we genotyped 154 patients with ATIN of different causes and 200 healthy controls at HLA-DQA1, -DQB1, and -DRB1 loci. We found that there was no difference between patients with D-ATIN and TINU in the carrier’s frequency of HLA-DQA1, -DQB1, or -DRB1. Patients with Sjogren’s syndrome–ATIN and IgG4-related ATIN presented a different pattern of tested HLA alleles. HLA-DQA1*0104 (p value corrected by false discovery rate method [Pc] = 4.72 × 10−22, odds ratio [OR] = 13.81), -DQB1*0503 (Pc = 1.95 × 10−14, OR = 9.51), and -DRB1*1405 (Pc = 8.06 × 10−19, OR = 12.80) were significant risk alleles for the occurrence of D-ATIN and TINU. There were no significant associations between tested HLA alleles and ATIN induced by other causes. Patients with D-ATIN/TINU carrying HLA-DQA1*0104/DQB1*0503/DRB1*1405 had higher peak serum creatinine and more severe renal tubulointerstitial inflammatory impairment. They also had significantly higher levels of tubular HLA-DR and HLA-DQ expression, which were correlated with the numbers of interstitial CD4+ T lymphocytes (r = 0.975, p < 0.001 and r = 0.832, p = 0.005, respectively) and monocytes/macrophages (r = 0.721, p = 0.004 and r = 0.615, p = 0.02, respectively). In conclusion, patients with D-ATIN or TINU have genetic susceptibility in HLA-DQA1, -DQB1, and -DRB1 alleles. HLA-DQA1*0104/DQB1*0503/DRB1*1405 serves as a significant risk haplotype for development of D-ATIN and TINU, which might facilitate renal tubulointerstitial inflammation by enhancing Ag-presenting capacity of renal tubular cells.

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