Tubulointerstitial Nephritis after Using a Sodium-glucose Cotransporter 2 Inhibitor.

We herein report a case of acute kidney injury (AKI) due to tubulointerstitial nephritis (TIN) after starting empagliflozin in a diabetic patient. The patient developed stage 1 AKI with proteinuria and elevated tubulointerstitial markers. A renal biopsy showed acute TIN with lymphocytic infiltration into the interstitium. The patient's renal function improved after discontinuation of empagliflozin and steroid administration. Sodium-glucose cotransporter 2 (SGLT2) inhibitor-induced AKI has been reported, but the underlying mechanism remains unclear, potentially because few patients with SGLT2-inhibitor-induced AKI have undergone a renal biopsy. We report the present case in the hope that it will help clarify the mechanism.

Prognostic factors for acute ischemic stroke in patients undergoing hemodialysis.

BACKGROUND: Acute ischemic stroke (AIS) is a critical complication in patients undergoing dialysis. Although the improvement of AIS management is an urgent requirement, few studies have evaluated the prognostic factors of AIS in these patients. This study aimed to assess the relationship between clinical factors in patients undergoing dialysis and the prognosis of AIS. METHODS: Among 1267 patients who were hospitalized for AIS in Sendai City Hospital from January 2015 to June 2020, 81 patients undergoing hemodialysis were retrospectively enrolled. Multivariate analysis was performed to evaluate the effect of baseline characteristics, dialysis factors, and neurological severity of patients at admission [National Institutes of Health Stroke Scale (NIHSS) score] on in-hospital mortality, physical disability, and the need for rehabilitation transfer. RESULTS: A higher NIHSS score was a critical risk factor for each outcome and the only significant factor for in-hospital mortality [odds ratio (OR)/point 1.156, 95% confidence interval (CI) 1.054-1.267]. The risk factors of physical disability were NIHSS score (OR/point 1.458, 95% CI 1.064-1.998), older age (OR/year 1.141, 95% CI 1.022-1.274), diabetic nephropathy (OR 7.096, 95% CI 1.066-47.218), and higher premorbid modified Rankin scale (mRS) score (OR/grade 2.144, 95% CI 1.155-3.978); while those of rehabilitation transfer were a higher NIHSS score (OR/point 1.253, 95% CI 1.080-1.455), dialysis vintage (OR/year 1.175, 95% CI 1.024-1.349), and intradialytic hypotension before onset (OR 5.430, 95% CI 1.320-22.338). CONCLUSIONS: Along with neurological severity, dialysis vintage, intradialytic hypotension, and diabetic nephropathy could worsen the prognosis of patients with AIS undergoing hemodialysis.

Impact of Immune-Modulatory Drugs on Regulatory T Cell.

Immunosuppression strategies that selectively inhibit effector T cells while preserving and even enhancing CD4FOXP3 regulatory T cells (Treg) permit immune self-regulation and may allow minimization of immunosuppression and associated toxicities. Many immunosuppressive drugs were developed before the identity and function of Treg were appreciated. A good understanding of the interactions between Treg and immunosuppressive agents will be valuable to the effective design of more tolerable immunosuppression regimens. This review will discuss preclinical and clinical evidence regarding the influence of current and emerging immunosuppressive drugs on Treg homeostasis, stability, and function as a guideline for the selection and development of Treg-friendly immunosuppressive regimens.

Functional roles of Otx2 transcription factor in postnatal mouse retinal development.

We previously reported that Otx2 is essential for photoreceptor cell fate determination; however, the functional role of Otx2 in postnatal retinal development is still unclear although it has been reported to be expressed in retinal bipolar cells and photoreceptors at postnatal stages. In this study, we first examined the roles of Otx2 in the terminal differentiation of photoreceptors by analyzing Otx2; Crx double-knockout mice. In Otx2+/-; Crx-/- retinas, photoreceptor degeneration and downregulation of photoreceptor-specific genes were much more prominent than in Crx-/- retinas, suggesting that Otx2 has a role in the terminal differentiation of the photoreceptors. Moreover, bipolar cells decreased in the Otx2+/-; Crx-/- retina, suggesting that Otx2 is also involved in retinal bipolar-cell development. To further investigate the role of Otx2 in bipolar-cell development, we generated a postnatal bipolar-cell-specific Otx2 conditional-knockout mouse line. Immunohistochemical analysis of this line showed that the expression of protein kinase C, a marker of mature bipolar cells, was significantly downregulated in the retina. Electroretinograms revealed that the electrophysiological function of retinal bipolar cells was impaired as a result of Otx2 ablation. These data suggest that Otx2 plays a functional role in the maturation of retinal photoreceptor and bipolar cells.

Cloning and characterization of mr-s, a novel SAM domain protein, predominantly expressed in retinal photoreceptor cells.

BACKGROUND: Sterile alpha motif (SAM) domains are approximately 70 residues long and have been reported as common protein-protein interaction modules. This domain is found in a large number of proteins, including Polycomb group (PcG) proteins and ETS family transcription factors. In this work, we report the cloning and functional characterization of a novel SAM domain-containing protein, which is predominantly expressed in retinal photoreceptors and the pineal gland and is designated mouse mr-s (major retinal SAM domain protein). RESULTS: mr-s is evolutionarily conserved from zebrafish through human, organisms through which the mechanism of photoreceptor development is also highly conserved. Phylogenetic analysis suggests that the SAM domain of mr-s is most closely related to a mouse polyhomeotic (ph) ortholog, Mph1/Rae28, which is known as an epigenetic molecule involved in chromatin modifications. These findings provide the possibility that mr-s may play a critical role by regulating gene expression in photoreceptor development. mr-s is preferentially expressed in the photoreceptors at postnatal day 3-6 (P3-6), when photoreceptors undergo terminal differentiation, and in the adult pineal gland. Transcription of mr-s is directly regulated by the cone-rod homeodomain protein Crx. Immunoprecipitation assay showed that the mr-s protein self-associates mainly through the SAM domain-containing region as well as ph. The mr-s protein localizes mainly in the nucleus, when mr-s is overexpressed in HEK293T cells. Moreover, in the luciferase assays, we found that mr-s protein fused to GAL4 DNA-binding domain functions as a transcriptional repressor. We revealed that the repression activity of mr-s is not due to a homophilic interaction through its SAM domain but to the C-terminal region. CONCLUSION: We identified a novel gene, mr-s, which is predominantly expressed in retinal photoreceptors and pineal gland. Based on its expression pattern and biochemical analysis, we predict that mr-s may function as a transcriptional repressor in photoreceptor cells and in pinealocytes of the pineal gland.

Micro serial analysis of gene expression in normal human choroid and retinal pigment epithelial transcriptomes.

PURPOSE: To investigate the gene expression profile of the normal human choroid/retinal pigment epithelium(RPE) tissues. METHODS: Micro serial analysis of gene expression (Micro SAGE) was performed. A SAGE library was constructed from 110 microg of total RNA of normal human choroid/RPE tissue, and cloned tag concatemers transformed to E.coli were sequenced. The sequence data were analyzed by SAGE software and matched to GenBank and UniGene public databases. The sequence data were also compared with the choroid/RPE cDNA library of NEIBank. RESULTS: A total of 12 070 tags were sequenced; 3627 tags were unique. Of these 3627 tags, 2508 tags were encoded genes and 1119 tags were unknown tags in the UniGene database. The most frequently expressed tag was TCCCTATTAA, but the gene corresponding to this tag has not been identified yet. Other frequently expressed tags encoded a tissue inhibitor of matrix metalloproteinase 3, insulin-like growth factor binding protein-related protein 1, and transthyretin. These genes are notably different, with high expression frequencies when compared to the cDNA library of NEIBank. CONCLUSIONS: This gene expression profile of the normal human choroid/RPE tissue should provide further understanding of the biological function of the choroid and the pathogenesis of diseases in which the choroid and RPE play a role, such as choroidal neovascularization.

Quinolone alkaloids with nitric oxide production inhibitory activity from Orixa japonica.

Four new quinolone alkaloids, orixalone A (1), B (2), C (3), and D (4), together with 12 known compounds were isolated from the stems of Orixa japonica. Orixalone A (1) inhibited nitric oxide production in murine macrophage-like RAW 264.7 cells stimulated with interferon-gamma and lipopolysaccharide.

Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development.

Understanding the molecular mechanisms by which distinct cell fate is determined during organogenesis is a central issue in development and disease. Here, using conditional gene ablation in mice, we show that the transcription factor Otx2 is essential for retinal photoreceptor cell fate determination and development of the pineal gland. Otx2-deficiency converted differentiating photoreceptor cells to amacrine-like neurons and led to a total lack of pinealocytes in the pineal gland. We also found that Otx2 transactivates the cone-rod homeobox gene Crx, which is required for terminal differentiation and maintenance of photoreceptor cells. Furthermore, retroviral gene transfer of Otx2 steers retinal progenitor cells toward becoming photoreceptors. Thus, Otx2 is a key regulatory gene for the cell fate determination of retinal photoreceptor cells. Our results reveal the key molecular steps required for photoreceptor cell-fate determination and pinealocyte development.

The mouse Crx 5'-upstream transgene sequence directs cell-specific and developmentally regulated expression in retinal photoreceptor cells.

Crx, an Otx-like homeobox gene, is expressed primarily in the photoreceptors of the retina and in the pinealocytes of the pineal gland. The CRX homeodomain protein is a transactivator of many photoreceptor/pineal-specific genes in vivo, such as rhodopsin and the cone opsins. Mutations in Crx are associated with the retinal diseases, cone-rod dystrophy-2, retinitis pigmentosa, and Leber's congenital amaurosis, which lead to loss of vision. We have generated transgenic mice, using 5'- and/or 3'-flanking sequences from the mouse Crx homeobox gene fused to the beta-galactosidase (lacZ) reporter gene, and we have investigated the promoter function of the cell-specific and developmentally regulated expression of Crx. All of the independent transgenic lines commonly showed lacZ expression in the photoreceptor cells of the retina and in the pinealocytes of the pineal gland. We characterized the transgenic lines in detail for cell-specific lacZ expression patterns by 5-bromo-4-chloro-3-indolyl beta-D-galactoside staining and lacZ immunostaining. The lacZ expression was observed in developing and developed photoreceptor cells. This observation was confirmed by coimmunostaining of dissociated retinal cells with the lacZ and opsin antibodies. The ontogeny analysis indicated that the lacZ expression completely agrees with a temporal expression pattern of Crx during retinal development. This study demonstrates that the mouse Crx 5'-upstream genomic sequence is capable of directing a cell-specific and developmentally regulated expression of Crx in photoreceptor cells.