Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-γ.

Maladaptive repair after AKI may lead to progressive fibrosis and decline in kidney function. Sphingosine 1-phosphate has an important role in kidney injury and pleiotropic effects in fibrosis. We investigated the involvement of sphingosine kinase 1 and 2 (SphK1 and SphK2), which phosphorylate sphingosine to produce sphingosine 1-phosphate, in kidney fibrosis induced by folic acid (FA) or unilateral ischemia-reperfusion injury. Analysis of Masson trichrome staining and fibrotic marker protein and mRNA expression 14 days after AKI revealed that wild-type (WT) and Sphk1-/- mice exhibited more kidney fibrosis than Sphk2-/- mice. Furthermore, kidneys of FA-treated WT and Sphk1-/- mice had greater immune cell infiltration and expression of fibrotic and inflammatory markers than kidneys of FA-treated Sphk2-/- mice. In contrast, kidneys of Sphk2-/- mice exhibited greater expression of Ifng and IFN-γ-responsive genes (Cxcl9 and Cxcl10) than kidneys of WT or Sphk1-/- mice did at this time point. Splenic T cells from untreated Sphk2-/- mice were hyperproliferative and produced more IFN-γ than did those of WT or Sphk1-/- mice. IFN-γ blocking antibody administered to Sphk2-/- mice or deletion of Ifng (Sphk2-/-Ifng-/- mice) blocked the protective effect of SphK2 deficiency in fibrosis. Moreover, adoptive transfer of Sphk2-/- (but not Sphk2-/-Ifng-/- ) CD4 T cells into WT mice blocked FA-induced fibrosis. Finally, a selective SphK2 inhibitor blocked FA-induced kidney fibrosis in WT mice. These studies demonstrate that SphK2 inhibition may serve as a novel therapeutic approach for attenuating kidney fibrosis.

Development and Implementation of a Longitudinal Global Acute Care and Systems Strengthening Program.

BACKGROUND: Increasing access to safe, timely, and affordable acute care in low- and middle-income countries is a worldwide priority. Longitudinal curricula on systems of acute care have not been previously described. OBJECTIVES: The authors aimed to develop a novel four-year longitudinal curriculum for medical students addressing systems development across multiple acute care specialties. METHODS: The authors followed Kern's six-step framework for curriculum design. After review of literature, a group of medical students and school of medicine faculty conducted a targeted needs assessment. Foundational goals and objectives were adapted from the 39 interprofessional global health competencies by the Consortium of Universities for Global Health. Educational strategies include didactic sessions, workshops, journal clubs, preceptorships, and community outreach. Clinical years include specialty-specific emphases, guided junior-level discussions, and a capstone project. Yearly SWOT and Kirkpatrick model analyses served as program evaluation. FINDINGS: The Curriculum Council approved the program in July 2019. During the first cycle, the program matriculated 30 students from classes of 2023 (14) and 2022 (16). The first year produced 11 interactive sessions, 6 journal clubs, and 10 seminars led by 31 faculty and guest speakers; 29/30 students completed requirements; 87 evaluations reflected 4.57/5 content satisfaction and 4.73/5 instructor satisfaction. The 2023 cohort reported improved understanding of session objectives (3.13/5 vs. 3.82/5, p = 0.03). Free-text feedback led to implementation of pre-reading standardization and activity outlines. CONCLUSION: The Program was well-received and successfully implemented. It meets the needs of graduating medical students interested in leading global health work. This novel student-faculty collaborative model could be applied at other institutions seeking to provide students with a foundation in global acute care.