Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral glucose-lowering agents. Apart from their glucose-lowering effects, large clinical trials assessing certain SGLT2 inhibitors have revealed cardiac and renal protective effects in non-diabetic patients. These excellent outcomes motivated scientists and clinical professionals to revisit their underlying mechanisms. In addition to the heart and kidney, redox homeostasis is crucial in several human diseases, including liver diseases, neural disorders, and cancers, with accumulating preclinical studies demonstrating the therapeutic benefits of SGLT2 inhibitors. In the present review, we aimed to update recent advances in the antioxidant roles of SGLT2 inhibitors in common but debilitating human diseases. We anticipate that this review will guide new research directions and novel therapeutic strategies for diabetes, cardiovascular diseases, nephropathies, liver diseases, neural disorders, and cancers in the era of SGLT2 inhibitors.

Background: Chronic kidney disease (CKD) is a global health threat affecting approximately 10% of the adult population worldwide. Multimorbidity is common in CKD, but its impacts on disease outcomes are seldom investigated. Methods: This prospective cohort analysis followed patients, who were part of a multidisciplinary CKD care program, for 10 years. We aimed to determine the impact of multimorbidity on renal outcomes. Results: Overall, 1463 patients with stage 3–5 CKD were enrolled and stratified by the number of comorbidities. Mean follow-up time was 6.39 ± 1.19 years. We found that stage 3–5 CKD patients with at least three comorbidities at enrollment initiated dialysis earlier (hazard ratio (HR): 2.971) than patients without comorbidities. Risk factors for multimorbidity included old age, smoking, and proteinuria. Conclusions: By analyzing the number of comorbidities, a simple and readily applicable method, we demonstrated an association between multimorbidity and poor renal outcomes in stage 3–5 CKD patients. In addition to current guideline-based approaches, our results suggest an urgent need for tailored CKD care strategies for high-risk groups.

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

Renal diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), have a great impact on health care systems worldwide. Similar to cardiovascular diseases, renal diseases are inflammatory diseases involving a variety of cytokines. Primary causes of renal injury include ischemia, uremic toxins, bacteremia, or nephrotoxicity. Inflammation represents an important component following kidney injury. Interleukin (IL)-33 is a member of the IL-1 cytokine family, which is widely expressed in epithelial barrier tissues and endothelial cells, and mediates both tissue inflammation and repair responses. IL-33 is released as a nuclear alarmin in response to tissue damage and triggers innate and adaptive immune responses by binding to its receptor, suppression of tumorigenicity 2 (ST2). Recent evidence from clinical and experimental animal studies indicates that the IL-33/ST2 axis is involved in the pathogenesis of CKD, renal graft injury, systemic lupus nephritis, and AKI. In this review, we discuss the pathological and tissue reparative roles of the IL-33/ST2 pathway in different types of renal diseases.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD). Elucidating the mechanisms underlying proteinuria in DKD is crucial because it is a common problem in DKD-related mortality and morbidity. MicroRNAs (miRs) associated with DKD have been detected in experimental diabetes models and in patients with both diabetes and CKD. Here, we aimed to investigate pathologic miRs in diabetic nephropathy (DN) by prospectively following six nephrotic, biopsy-proven isolated DN patients (enrolled between August 2015 and July 2017) for one year. The urinary exosomes were isolated at the time of the biopsy and the contained miRs were analyzed by next-generation sequencing. The results were compared to the control group, composed of age-, gender-, and CKD stage-matched patients with proteinuric CKD who did not present diabetes. Among the 72 identified miRs, we investigated eight (miR-188-5p, miR-150-3p, miR-760, miR-3677-3p, miR-548ah-3p, miR-548p, miR-320e, and miR-23c) exhibiting the strongest upregulation (13–15 fold) and two (miR-133a-3p and miR-153-3p) with the strongest downregulation (7–9 fold). The functional analysis of these miRs showed that they were involved in known and novel pathways of DN, supporting their pathologic roles. The bioinformatics-based prediction of the target genes of these miRs will inspire future research on the mechanisms underlying DN pathogenesis.

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses. IL-33 triggers pleiotropic immune functions in multiple types of immune cells, which express the IL-33 receptor, ST2. Recent studies have revealed the potential applications of IL-33 for treating acute kidney injury in preclinical animal models. However, IL-33 and IL-33-responding immune cells are reported to exhibit both detrimental and beneficial roles. The IL-33-mediated immunomodulatory functions have been investigated using loss-of-function approaches, such as IL33-deficient mice, IL-33 antagonists, or administration of exogenous IL-33 recombinant protein. This review will discuss the key findings on IL-33-mediated activation of kidney resident group 2 innate lymphoid cells (ILC2s) and summarize the current understanding of the differential functions of endogenous IL-33 and exogenous IL-33 and their potential implications in treating acute kidney injury.