The Cardiovascular–kidney–metabolic (CKM) syndrome, a concept recently proposed by the American Heart Association (AHA), highlights the intricate connection between metabolic, renal, and cardiovascular illnesses. Furthermore, the Atherogenic Index of Plasma (AIP), a useful biomarker for evaluating the risk of Cardiovascular Diseases (CVDs), has been associated with the risk of Adverse Cardiovascular Events (ACEs). Nonetheless, its precise function in populations in CKM syndrome Stages 0–3 remains unknown. This prospective study analyzed the data of 7,708 eligible participants (aged ≥ 45 years) from the Chinese Longitudinal Research of Ageing (CHARLS), particularly the 2011–2012 baseline survey (Wave 1). The primary exposure variable was AIP—a natural logarithm of the ratio of Triglycerides (TGs) to High-Density Lipoprotein Cholesterol (HDL-C). On the other hand, the primary endpoint was CVD incidence, which was determined based on self-reported past diagnoses. The relationship between AIP and CVD risk in the population in CKM syndrome stages 0–3 was examined using a Cox proportional risk model. Subgroup and mediation analyses were performed to further elucidate the interactions among these factors. This study involved 7,708 participants in the CKM syndrome stages 0–3 [Mean age = 58.00 years; Interquartile Range (IQR) = 52.00–65.00 years]. The risk of developing CVD increased significantly with higher AIP levels. Specifically, the risk ratio for each unit increase in AIP was 1.31 (95% CI 1.11–1.55), while the Hazard Ratio (HR) for the group with the highest AIP levels compared to the group with the lowest AIP levels was 1.22 (95% CI 1.08–1.39). Mediation analysis revealed that metabolic syndrome accounted for 12.3% of the association between AIP levels and CVD risk (p = 0.024), highlighting its significance in CVD risk assessment. Herein, AIP levels correlated significantly positively with CVD risk in individuals in CKM stages 0–3, with metabolic syndrome as a key mediating factor. These findings suggest that AIP levels could be valuable not only for CVD risk assessment but also for clinical screening.

Diabetic nephropathy (DN) is manifested as increased urinary protein level, decreased glomerular filtration rate, and final renal dysfunction. DN is the leading cause of end-stage renal disease worldwide and causes a huge societal healthcare burden. Since satisfied treatments are still limited, exploring new strategies for the treatment of this disease is urgently needed. Oxidative stress takes part in the initiation and development of DN. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the cellular response to oxidative stress. Thus, activation of Nrf2 seems to be a new choice for the treatment of DN. In current review, we discussed and summarized the therapeutic effects of Nrf2 activation on DN from both basic and clinical studies.

One of the commonest causes of end-stage renal disease is diabetic kidney disease (DKD). Renal fibrosis, characterized by the accumulation of extracellular matrix (ECM) proteins in glomerular basement membranes and the tubulointerstitium, is the final manifestation of DKD. The TGF-βpathway triggers epithelial-to-mesenchymal transition (EMT), which plays a key role in the accumulation of ECM proteins in DKD. DCCT/EDIC studies have shown that DKD often persists and progresses despite glycemic control in diabetes once DKD sets in due to prior exposure to hyperglycemia called “metabolic memory.” These imply that epigenetic factors modulate kidney gene expression. There is evidence to suggest that in diabetes and hyperglycemia, epigenetic histone modifications have a significant effect in modulating renal fibrotic and ECM gene expression induced by TGF-β1, as well as its downstream profibrotic genes. Histone modifications are also implicated in renal fibrosis through its ability to regulate the EMT process triggered by TGF-βsignaling. In view of this, efforts are being made to develop HAT, HDAC, and HMT inhibitors to delay, stop, or even reverse DKD. In this review, we outline the latest advances that are being made to regulate histone modifications involved in DKD.

Pyroptosis is a recently identified type of lytic programmed cell death, in which pores form in the plasma membrane, and cells swell, rupture, and then release their contents, including inflammatory cytokines. Molecular studies indicated that pyroptosis may occur via a gasdermin D (GSDMD) and caspase-1 (Casp1) -dependent classical pathway, a GSDMD and Casp11/4/5-dependent non-classical pathway, or a gasdermin E (GSDME) and Casp3-dependent pathway. Studies of animal models and humans indicated that pyroptosis can exacerbate several complications of diabetes, including diabetic nephropathy (DN), a serious microvascular complication of diabetes. Many studies investigated the mechanism mediating the renoprotective effect of GSDMD regulation in the kidneys of patients and animal models with diabetes. As a newly discovered regulatory mechanism, GSDME and Casp3-dependent pyroptotic pathway in the progression of DN has also attracted people’s attention. Z-DEVD-FMK, an inhibitor of Casp3, ameliorates albuminuria, improves renal function, and reduces tubulointerstitial fibrosis in diabetic mice, and these effects are associated with the inhibition of GSDME. Studies of HK-2 cells indicated that the molecular and histological features of secondary necrosis were present following glucose stimulation due to GSDME cleavage, such as cell swelling, and release of cellular contents. Therefore, therapies targeting Casp3/GSDME-dependent pyroptosis have potential for treatment of DN. A novel nephroprotective strategy that employs GSDME-derived peptides which are directed against Casp3-induced cell death may be a key breakthrough. This mini-review describes the discovery and history of research in this pyroptosis pathway and reviews the function of proteins in the gasdermin family, with a focus on the role of GSDME-mediated pyroptosis in DN. Many studies have investigated the impact of GSDME-mediated pyroptosis in kidney diseases, and these studies used multiple interventions, in vitro models, and in vivo models. We expect that further research on the function of GDSME in DN may provide valuable insights that may help to improve treatments for this disease.