The teleology of sex differences has been argued since at least as early as Aristotle’s controversial Generation of Animals more than 300 years BC, which reflects the sex bias of the time to contemporary readers. Although the question “why are the sexes different” remains a topic of debate in the present day in metaphysics, the recent emphasis on sex comparison in research studies has led to the question “how are the sexes different” being addressed in health science through numerous observational studies in both health and disease susceptibility, including blood pressure regulation and hypertension. These efforts have resulted in better understanding of differences in males and females at the molecular level that partially explain their differences in vascular function and renal sodium handling and hence blood pressure and the consequential cardiovascular and kidney disease risks in hypertension. This review focuses on clinical studies comparing differences between men and women in blood pressure over the life span and response to dietary sodium and highlights experimental models investigating sexual dimorphism in the renin-angiotensin-aldosterone, vascular, sympathetic nervous, and immune systems, endothelin, the major renal sodium transporters/exchangers/channels, and the impact of sex hormones on these systems in blood pressure homeostasis. Understanding the mechanisms governing sex differences in blood pressure regulation could guide novel therapeutic approaches in a sex-specific manner to lower cardiovascular risks in hypertension and advance personalized medicine.

The mainstay of therapy for chronic kidney disease is control of blood pressure and proteinuria through the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) that were introduced more than 20 years ago. Yet, many chronic kidney disease (CKD) patients still progress to end-stage kidney disease—the ultimate in failed prevention. While increased oxidative stress is a major molecular underpinning of CKD progression, no treatment modality specifically targeting oxidative stress has been established clinically. Here, we review the influence of oxidative stress in CKD, and discuss regarding the role of the Nrf2 pathway in kidney disease from studies using genetic and pharmacologic approaches in animal models and clinical trials. We will then focus on the promising therapeutic potential of sulforaphane, an isothiocyanate derived from cruciferous vegetables that has garnered significant attention over the past decade for its potent Nrf2-activating effect, and implications for precision medicine.

Significance Statement: GSTM1 encodes a member of a superfamily of antioxidant enzymes, and a highly prevalent GSTM1 deletion variant is associated with kidney disease progression in two human study cohorts. In this study, the authors demonstrate that Gstm1 knockout mice exhibit increased oxidative stress, kidney injury, and inflammation in models of CKD and hypertension, and that Gstm1 loss in the parenchyma but not in bone marrow–derived cells drives renal inflammation. Importantly, consumption of broccoli powder or cruciferous vegetables was protective against kidney disease only in Gstm1 knockout mice, and was observed mainly in the human participants in the Atherosclerosis Risk in Communities Study who were homozygous for GSTM1 deletion. These findings suggest that targeting antioxidant therapy specifically in individuals carrying the GSTM1 deletion variant may be effective in delaying kidney disease progression. Background: GSTM1 encodes glutathione S-transferase μ-1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent GSTM1 deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study. Methods: We generated a Gstm1 knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and GSTM1 genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic GSTM1 on renal inflammation. Results: Gstm1 knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that Gstm1 deletion in the parenchyma, and not in bone marrow–derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in Gstm1 knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the GSTM1 deletion variant. Conclusions: Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.

Blood tests are vital to prevention, diagnosis, and management of chronic diseases. Despite this, it can be challenging to construct a comprehensive view of the clinical importance of blood testing because relevant literature is typically fragmented across different disease areas and patient populations. This lack of collated evidence can also make it difficult for primary care providers to adhere to best practices for blood testing across different diseases and guidelines. Thus, this review article synthesizes the recommendations for, and importance of, blood testing across several common chronic conditions encountered in primary care and internal medicine, including cardiovascular diseases, diabetes mellitus, chronic kidney disease, vitamin D deficiency, iron deficiency, and rheumatoid arthritis. Future research is needed to continue improving chronic disease management through clearer dissemination and awareness of clinical guidelines among providers, and better access to blood testing for patients (e.g., via pre-visit laboratory testing).

There is higher prevalence of chronic kidney disease (CKD) in burn patients after hospital discharge; however, the cause remains unclear. This study aimed to investigate the lasting impacts of severe burns on the kidneys and to explore potential treatments. The study examined the effects of burning on healthy mice and adenine-induced CKD mice. Subsequently, the investigation focused on assessing the effects of activated macrophages on podocytes. Finally, the study evaluated the effectiveness of dexamethasone in mitigating the impacts of burns on the kidneys. In healthy mice, burns caused only subclinical signs in the kidneys. However, in the CKD group, burns not only reduced kidney function, but also aggravated kidney injuries, apoptosis, and inflammation. Moreover, the expression of Caspase-1 and -3 signalings was significantly increased in all mice after burns. Electron microscopy revealed that burns exacerbated glomerular injury in the CKD group, including podocyte injury, cell membrane blebbing, and rupture. Furthermore, polarized M1 macrophages led to increased MPC5 podocyte death. Following dexamethasone intervention, kidney function and injuries were alleviated in CKD mice. Severe burns can trigger PANoptosis by activating inflammation-induced Caspase-dependent pathways, which can lead to kidney injury in mice. This impairment is exacerbated in the CKD group. However, the administration of dexamethasone can effectively ameliorate kidney injury. These findings have significant implications for predicting the prognosis of kidney function in burn patients and offer a potential therapeutic approach.

Extracellular vesicles (EVs) are evolving as novel cell mediators, biomarkers, and therapeutic targets in kidney health and disease. They are naturally derived from cells both within and outside the kidney and carry cargo which mirrors the state of the parent cell. Thus, they are potentially more sensitive and disease-specific as biomarkers and messengers in various kidney diseases. Beside their role as novel communicators within the nephron, they likely communicate between different organs affected by various kidney diseases. Study of urinary EVs (uEVs) can help to fill current knowledge gaps in kidney diseases. However, separation and characterization are challenged by their heterogeneity in size, shape, and cargo. Fortunately, more sensitive and direct EV measuring tools are in development. Many clinical syndromes in nephrology from acute to chronic kidney and glomerular to tubular diseases have been studied. Yet, validation of biomarkers in larger cohorts is warranted and simpler tools are needed. Translation from in vitro to in vivo studies is also urgently needed. The therapeutic role of uEVs in kidney diseases has been studied extensively in rodent models of AKI. On the basis of the current exponential growth of EV research, the field of EV diagnostics and therapeutics is moving forward.