Commentary
Abstract
Clinically, potassium supplementation has been shown to lower blood pressure and reduce the risk of stroke through modulation of potassium excretion and sodium reabsorption. Hypokalemia activates the renal sodium chloride cotransporter (NCC) along the distal convoluted tubule (DCT), at least in part, through with-no-lysine 4 (WNK4) kinase and STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) signaling. The DCT also expresses a kinase-deficient, kidney-specific form of WNK1 (KS-WNK1), but its role in NCC activation is unclear. In this issue of the JCI, Boyd-Shiwarski and colleagues found that KS-WNK1 enhanced the effects of potassium on NCC activation in vivo. Specifically, they showed that mice lacking KS-WNK1 did not respond as robustly to dietary challenge. Additionally, in vivo expression of a mutated KS-WNK1 disrupted WNK body, or biomolecular condensate, formation and renal function. These findings, along with those of previous studies, indicate that KS-WNK1 may regulate potassium homeostasis by increasing the kidney’s sensitivity to salt-dependent stress.
Authors
Gerardo Gamba, David H. Ellison
Abstract
Cellular susceptibility to HIV is associated with integrin α4β7, a mucosal homing receptor involved with trafficking HIV target cells to sites of HIV replication. However, studies investigating preinfection α4β7 expression as a predictor of HIV outcomes have yielded inconsistent findings, raising questions about the role of α4β7 in HIV acquisition across populations. In this issue of the JCI, Machmach et al. assessed PBMCs collected before HIV infection and found higher α4β7 expression on memory CD4+ T cells and invariant NK T (iNKT) cells in individuals who went on to acquire HIV. Here, we consider possible explanations that may underlie discrepancies among studies and suggest that α4β7 should be considered as part of a multifactorial profile for determining HIV risk. While unlikely to serve as a target for HIV prevention or therapy, α4β7-directed interventions may offer adjunctive benefits in preserving or improving mucosal immunity.
Authors
Tosin E. Omole, Lyle R. McKinnon
Abstract
Kidney stone disease (KSD) arises from a complex interplay of genetic predisposition, diet, metabolic disorders, and other environmental factors. In this issue of the JCI, Lovegrove et al. report a large GWAS that identifies 71 loci associated with an increased risk of KSD. Through an integrative approach combining Mendelian randomization and functional validation, they emphasize the roles of DGKD, SLC34A1, and CYP24A1 in maintaining homeostasis of calcium and phosphate. These findings offer insights into the pathogenesis of KSD and suggest potential targets for intervention. Further studies are needed to validate these findings across diverse populations and clinical settings.
Authors
Shiwei Li, Xuemei Wang, Ming Liu
Abstract
Pain is a serious medical condition with current treatments remaining limited by side effects. The Nav1.7 voltage-gated sodium channel is a crucial determinant of nociceptor excitability and a promising target for nonaddictive analgesics. However, development of blockers has been difficult. In this issue of the JCI, Singh, Bernabucci, and authors identify a strategy for reducing Nav1.7 currents. These findings identify fibroblast growth factor 13 (FGF13), a homologous factor distinct from typical growth factors (also known as FHF2B), which ramps up Nav1.7, nociceptor excitability, and pain. Compound PW164 was identified as a selective FGF13-Nav1.7 attenuator with analgesic activity. These findings highlight the power of targeting intrinsic modulators of Nav1.7 for pain management.
Authors
Theodore R. Cummins
Abstract
Purine nucleotides are critical for nucleic acid synthesis, signaling, and cellular metabolism. Thiopurines (TPs), including 6-mercaptopurine and 6-thioguanine, are cornerstone agents for the treatment of acute lymphoblastic leukemia (ALL). TP efficacy and cytotoxicity depend on the metabolism and intracellular activation of TPs, a process influenced by pharmacogenes such as thiopurine-S methyltransferase (TPMT) and NUDIX (nucleoside diphosphates linked to moiety-X) hydrolase 15 (NUDT15). In this issue of the JCI, Maillard et al. identified NUDT5 as a determinant of TP pharmacology. They demonstrated that loss of NUDT5 conferred TP resistance by impairing drug activation and DNA damage responses. Metabolomics studies by Maillard and others revealed that NUDT5 may regulate the balance between the de novo purine synthesis and salvage pathways. Clinically, NUDT5 expression variants were associated with altered TP tolerance. These findings position NUDT5 as a key modulator of nucleotide metabolism and TP efficacy, with potential implications for pharmacogenomics-guided therapy optimization in ALL.
Authors
Leo Kager, Kaan Boztug
Abstract
T cell–mediated rejection (TCMR) develops after alloantigen-primed T cells migrate into an allograft to cause tissue damage. In contrast to antibody-mediated rejection, which creates lesions in the graft vasculature, injury to the graft vasculature is often limited during TCMR. In this issue of the JCI, Barba et al. investigated the mechanism by which the endothelium is spared from harm caused by graft-infiltrating CD8+ T cells. Endothelial cell protection was due to cell-extrinsic chemokine variations in the environment, rather than cell-intrinsic differences between endothelial and interstitial cells. The CXCL12 gradient in particular facilitated CD8+ T cell movement through the endothelial layer into the graft parenchyma. These findings suggest that targeting the CXCL12 pathway may prevent or alleviate TCMR.
Authors
Scott M. Krummey, Jonathan S. Bromberg
Abstract
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, presents a clinical challenge in developing effective treatment options. In this issue of the JCI, Zeng et al. demonstrate a provocative and promising therapeutic strategy for TNBC by leveraging the metabolic vulnerabilities presented by methylthioadenosine phosphorylase (MTAP) deletion to genotoxic stress inducers, such as poly (ADP-ribose) polymerase inhibitors (PARPi). They found that combining MTAP deletion or inhibition with PARPi was highly effective in brain metastatic TNBC where the methionine-limited environment further enhanced this combination. This approach underscores the importance of targeting metabolic vulnerabilities in the development of personalized cancer therapies.
Authors
Samyuktha Suresh, James M. Ford
Abstract
Recent studies have highlighted a possible role for gut microbiota in modulating Alzheimer’s disease pathology, particularly through the actions of gut-derived metabolites and their influence on the immune system. In this issue of the JCI, Chandra et al. reveal that circulating levels of the gut microbiota–derived metabolite propionate affected amyloid burden and glial activation in a mouse model of Aβ amyloidosis. The study also identifies a mechanism for the therapeutic benefit of propionate supplementation, showing that propionate lowered peripheral IL-17 and suppressed Th17 cell activity. These results support the idea of therapeutic targeting of the gut/brain/immune axis, particularly via modulation of Th17 responses, and suggest translational strategies involving microbiome-based or immunological interventions for dementia prevention and treatment.
Authors
Wade K. Self, David M. Holtzman
Abstract
Bardet-Biedl syndrome (BBS) is a complex genetic condition that can affect multiple organ systems, frequently causing pigmentary retinopathy, renal abnormalities, polydactyly, and obesity. Metabolic disturbances including obesity, unsuppressed appetite, and an increased risk of type 2 diabetes (T2D) present clinical management challenges. In this issue of the JCI, Singh et al. present a mouse model of a specific BBS subtype with genetic deletion of the Bbs5 gene. The model recapitulates many of the clinical features observed in patients living with BBS5 and sheds light on adipocyte biology, as well as the hypothalamic mechanisms driving hunger- and food-seeking behaviors that fuel the adverse metabolic phenotype. Importantly, exogenous GLP-1 receptor agonist treatment suppressed both appetite and weight, opening opportunities for direct translation into the clinical setting.
Authors
Jeremy W. Tomlinson
Abstract
Uromodulin is the most abundant protein in human urine, playing diverse roles, from providing frontline defense against uropathogens to regulating electrolyte balance via modulation of ion channels and cotransporters. In this issue of the JCI, Nanamatsu et al. unveil an alternatively spliced isoform of uromodulin that was dynamically induced in response to oxidative stress and tubular injury. Unlike the canonical secreted form, this isoform was retained in the cell, where it interacted with solute carrier proteins primarily localized to the mitochondrial membrane. Through these interactions, it modulated mitochondrial energetics and enhanced tubular cell resilience to injury. These findings broaden our understanding of uromodulin’s multifaceted functions, uncover an adaptive mechanism by which the kidney responds to cellular stress, and open avenues for therapeutic strategies targeting kidney injury and repair.
Authors
Ronak Lakhia, Chunzi Song, Vishal Patel
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