Acute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic-reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal... Show moreAcute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic-reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal tubules (PT) is lost to the tubular lumen. How injured tubules reconstitute lost membrane lipids during renal recovery is not known. Here, we identified Mfsd2a, a sodium-dependent lysophosphatidylcholine (LPC) transporter, to be expressed specifically in the basolateral membrane of S3 PT. Using an in vivo activity probe for Mfsd2a, transport activity was found to be specific to the S3 PT. Mice with haploinsufficiency of Mfsd2a exhibited delayed recovery of renal function after acute IRI, with depressed urine osmolality and elevated levels of histological markers of damage, fibrosis, and inflammation, findings corroborated by transcriptomic analysis. Lipidomics revealed a deficiency in docosahexaenoic acid (DHA) containing phospholipids in Mfsd2ahaploinsufficiency. Treatment of Mfsd2ahaploinsufficient mice with LPC-DHA improved renal function and reduced markers of injury, fibrosis, and inflammation. Additionally, LPC-DHA treatment restored S3 brush border membrane architecture and normalized DHA-containing phospholipid content. These findings indicate that Mfsd2a-mediated trans-port of LPC-DHA is limiting for renal recovery after AKI and suggest that LPC-DHA could be a promising dietary supplement for improving recovery following AKI. Show less
Solute carrier transporters (SLCs) limit receptor activation via uptake of extracellular ligands. Novel concepts are emerging that describe the modulation of intracellular and plasma membrane... Show moreSolute carrier transporters (SLCs) limit receptor activation via uptake of extracellular ligands. Novel concepts are emerging that describe the modulation of intracellular and plasma membrane receptors by ligand influx and efflux via SLCs, respectively. Here, we evaluate recent insights and provide an outlook for developing potential therapeutic strategies. Show less
The study of immunity against Transporter Associated with Antigen Processing (TAP)-deficient cells led to the discovery of peptides presented by such TAP-deficient cells. Some of these peptides... Show moreThe study of immunity against Transporter Associated with Antigen Processing (TAP)-deficient cells led to the discovery of peptides presented by such TAP-deficient cells. Some of these peptides constituted antigens to Cytotoxic T-lymphocytes (CTL) and these CTL only recognized TAP-deficient cells but not normal cells. These peptides were called __T-cell epitopes associated with impaired peptide processing__ (TEIPP). Therefore, TEIPP corresponds to immunogenic peptides that are presented only in cases of processing deficiency and not by normal cells. The studies of TEIPP antigens thus far have revealed that these antigens are promising candidates for the combat of immune escaped tumors. However, several aspects about TEIPPs needed clarification: what are the processing pathways that lead to generation and presentation of TEIPP antigens; what is the mechanism behind the immunogenicity of TEIPP; what are the charac teristics of TEIPP peptides presented by non-classical Major Histocompatibility Complex class I (MHC-I) molecules. The studies presented in this thesis are focused on these topics Show less
