Nephrology
Abstract
Graft endothelial cells (ECs) express donor alloantigens and encounter cytotoxic T lymphocytes (CTLs) but are generally spared during T cell-mediated rejection (TCMR), which predominantly affects epithelial structures. The mechanisms underlying this vascular immune privilege are unclear. Transcriptomic analyses and endothelial-mesenchymal transition assessments confirmed that the graft endothelium is preserved during TCMR. Co-culture experiments revealed that endothelial and epithelial cells are equally susceptible to CTL-mediated lysis, ruling out cell-intrinsic protection. Intravital microscopy of murine kidney grafts and single-cell RNA sequencing of human renal allografts demonstrated that CTL interactions with ECs are transient compared to epithelial cells. This disparity is mediated by a chemotactic gradient produced by graft stromal cells, guiding CTLs away from ECs toward epithelial targets. In vitro, chemotaxis overrode TCR-induced cytotoxicity, preventing endothelial damage. Finally, analysis of TCMR biopsies revealed that disruption of the chemotactic gradient correlates with endothelialitis lesions, linking its loss to vascular damage. These findings challenge the traditional view of cell-intrinsic immune privilege, proposing a cell-extrinsic mechanism where chemotaxis preserves graft vasculature during TCMR. This mechanism may have implications beyond transplantation, highlighting its role in maintaining vascular integrity across pathological conditions.
Authors
T. Barba, M. Oberbarnscheidt, G. Franck, C. Gao, S. This, M. Rabeyrin, C. Roufosse, L. Moran, A. Koenig, V. Mathias, C. Saison, V. Dubois, N. Pallet, D. Anglicheau, B. Lamarthée, A. Hertig, E. Morelon, A Hot, H. Paidassi, T. Defrance, A. Nicoletti, J.P. Duong-Van-Huyen, Y. Xu-Dubois, F.G. Lakkis, O. Thaunat
Abstract
BACKGROUND. Kidney stone disease (KSD) affects ~10% of adults, is heritable, and associated with mineral metabolic abnormalities. METHODS. Genetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using genome-wide association analyses, region-specific Mendelian randomization (MR), and genetic colocalization. Utility of pathway modulation was estimated via drug-target MR, and effects of variants on calcium-sensing receptor (CaSR)-signaling characterized. RESULTS. Seventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified three loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (odds ratios for genomic regions=4.30, 11.42, and 13.83 per 1 standard deviation alteration; p<5.6x10-10). Colocalization analyses defined putative, non-coding KSD-causing variants estimated to account for 11-19% of KSD cases in proximity to diacylglycerol kinase delta (DGKD), a CaSR-signalling partner; solute carrier family 34 member 1 (SLC34A1), a renal sodium-phosphate transporter; and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), which degrades 1,25-dihydroxyvitamin D. Drug- target MR indicated that reducing serum calcium by 0.08mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16mmol/L via SLC34A1 may reduce KSD relative risk by up to 90%. Furthermore, reduced DGKδ expression and KSD-associated DGKD missense variants impaired CaSR-signal transduction in vitro, which was ameliorated by cinacalcet, a positive CaSR-allosteric modulator. CONCLUSION. DGKD-, SLC34A1-, and CYP24A1-associated variants linked to reduced CaSR-signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation, respectively, are common causes of KSD. Genotyping patients with KSD may facilitate personalised KSD-risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.
Authors
Catherine E. Lovegrove, Michelle Goldsworthy, Jeremy Haley, Diane Smelser, Caroline Gorvin, Fadil M. Hannan, Anubha Mahajan, Mohnish Suri, Omid Sadeghi-Alavijeh, Shabbir H. Moochhala, Daniel P. Gale, David Carey, Michael V. Holmes, Dominic Furniss, Rajesh V. Thakker, Sarah A. Howles
Abstract
The ATP6V0A4 gene encodes the a4 subunit of Vacuolar H+-ATPase (V-ATPase), which mediates hydrogen ion transport across the membrane. Previous studies have suggested that mutations in ATP6V0A4 consistently result in a loss of function (LOF), impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis (dRTA) and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous ATP6V0A4 p.V512L mutation, and both exhibited with hypochloremic metabolic alkalosis, acidic urine and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function (GOF) mutation in the ATP6V0A4 gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated V-ATPase's capacity to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we discovered F351 (C25H26FN3O2S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identify a GOF mutation in the ATP6V0A4 gene, broadening its phenotypic and mutational spectrum, and provide valuable insights into potential therapeutic approaches for diseases associated with ATP6V0A4 mutations.
Authors
Si-qi Peng, Qian-qian Wu, Wan-yi Wang, Yi-Lin Zhang, Rui-ning Zhou, Jun Liao, Jin-xuan Wei, Yan Yang, Wen Shi, Jun-lan Yang, Xiao-xu Wang, Zhi-yuan Wei, Jia-xuan Sun, Lu Huang, Hong Fan, Hui Cai, Cheng-kun Wang, Xin-hua Li, Ting-song Li, Bi-Cheng Liu, Xiao-liang Zhang, Bin Wang
Abstract
Authors
Michaela A.A. Fuchs, Myles Wolf
Abstract
Authors
Sandrine Lemoine, Arnaud Molin, Alice Koenig, Justine Bacchetta
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI183343.
Abstract
In the kidney, cells of thick ascending limb of the loop of Henle (TAL) are resistant to ischemic injury, despite high energy demands. This adaptive metabolic response is not fully understood even though the integrity of TAL cells is essential for recovery from acute kidney injury (AKI). TAL cells uniquely express uromodulin, the most abundant protein secreted in healthy urine. Here, we demonstrate that alternative splicing generates a conserved intracellular isoform of uromodulin, which contributes to metabolic adaptation of TAL cells. This splice variant was induced by oxidative stress and was up-regulated by AKI that is associated with recovery, but not by severe AKI and chronic kidney disease (CKD). This intracellular variant was targeted to the mitochondria, increased NAD+ and ATP levels, and protected TAL cells from hypoxic injury. Augmentation of this variant using antisense oligonucleotides after severe AKI improved the course of injury. These findings underscore an important role of condition-specific alternative splicing in adaptive energy metabolism to hypoxic stress. Enhancing this protective splice variant in TAL cells could become a novel therapeutic intervention for AKI.
Authors
Azuma Nanamatsu, George J. Rhodes, Kaice A. LaFavers, Radmila Micanovic, Virginie Lazar, Shehnaz Khan, Daria Barwinska, Shinichi Makino, Amy Zollman, Ying-Hua Cheng, Emma H. Doud, Amber L. Mosley, Matthew J. Repass, Malgorzata M. Kamocka, Aravind Baride, Carrie L. Phillips, Katherine J. Kelly, Michael T. Eadon, Jonathan Himmelfarb, Matthias Kretzler, Robert L. Bacallao, Pierre C. Dagher, Takashi Hato, Tarek M. El-Achkar
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI190850.
Abstract
Background: Men with chronic kidney disease (CKD) experience faster kidney function decline than women. Studies in individuals undergoing sex hormone therapy suggest a role for sex hormones, as estimated glomerular filtration rate (eGFR) increases with feminizing therapy and decreases with masculinizing therapy. However, effects on measured GFR (mGFR), glomerular and tubular function, and involved molecular mechanisms remain unexplored. Methods: This prospective, observational study included individuals initiating feminizing (estradiol and antiandrogens; n=23) or masculinizing (testosterone; n=21) therapy. Baseline and three-month assessments included mGFR (Iohexol clearance), kidney perfusion (para-aminohippuric acid clearance), tubular injury biomarkers, and plasma proteomics. Results: During feminizing therapy, mGFR and kidney perfusion increased (+3.6% and +9.1%, respectively; p<0.05), without increased glomerular pressure. Tubular injury biomarkers, including urine neutrophil gelatinase-associated lipocalin, EGF, monocyte chemoattractant protein-1, and chitinase 3-like protein 1 (YKL-40), decreased significantly (-53%, -42%, -45%, and -58%, respectively). During masculinizing therapy, mGFR and kidney perfusion remained unchanged, but urine YKL-40 and plasma TNFR-1 increased (+134% and +8%, respectively; p<0.05). Proteomic analysis revealed differential expression of 49 proteins during feminizing, and 356 proteins during masculinizing therapy. Many kidney-protective proteins were positively associated with estradiol and negatively associated with testosterone, including proteins involved in endothelial function (SFRP4, SOD3), inflammation reduction (TSG-6), and maintaining kidney tissue structure (agrin). Conclusion: Sex hormones influence kidney physiology, with estradiol showing protective effects on glomerular and tubular function, while testosterone predominantly exerts opposing effects. These findings emphasize the role of sex hormones in sexual dimorphism observed in kidney function and physiology and suggest new approaches for sex-specific precision medicine.
Authors
Sarah A. van Eeghen, Laura Pyle, Phoom Narongkiatikhun, Ye Ji Choi, Wassim Obeid, Chirag R. Parikh, Taryn G. Vosters, Irene GM van Valkengoed, Merle M. Krebber, Daan J. Touw, Martin den Heijer, Petter Bjornstad, Daniël Raalte, Natalie J. Nokoff
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI181164.
Abstract
Aberrant O-glycosylation of the IgA1 hinge region is a characteristic finding in patients with IgA nephropathy (IgAN) and is thought to contribute to immune-complex formation and kidney injury. Other studies have suggested that abnormalities in mucosal immunity and lymphocyte homing are major contributors to disease. We identified a family with IgAN segregating a heterozygous predicted loss-of-function (LOF) variant in GALNT14, the gene encoding N-acetylgalactosaminyltransferase 14, one of the enzymes involved in mucin-type protein O-glycosylation. While GALNT14 is expressed in IgA1-producing cells, carriers of the LOF variant did not have altered levels of poorly glycosylated IgA1, suggesting other disease mechanisms. Investigation of Galnt14 null mice revealed elevated serum IgA levels and ex vivo IgA production by B cells. These mice developed glomerular IgA deposition with aging and after induction of sterile colitis. Galnt14 null mice also displayed an attenuated mucin layer in the colon and redistribution of IgA-producing cells from mucosal to systemic sites. Adoptive-transfer experiments indicated impaired homing of spleen-derived Galnt14 deficient B lymphocytes, resulting in increased retention in peripheral blood. These findings suggest that abnormalities in O-glycosylation alter mucosal immunity and B lymphocyte homing, pointing to an expanded role of aberrant O-glycosylation in the pathogenesis of IgAN.
Authors
Sindhuri Prakash, Nicholas J. Steers, Yifu Li, Elena Sanchez-Rodriguez, Miguel Verbitsky, Isabel Robbins, Jenna Simpson, Sharvari Pathak, Milan Raska, Colin Reily, Anna Ng, Judy Liang, Natalia DeMaria, Amanda Katiraei, Kelsey O'Stevens, Clara Fischman, Samantha Shapiro, Swetha Kodali, Jason McCutchan, Heekuk Park, Djamila Eliby, Marco Delsante, Landino Allegri, Enrico Fiaccadori, Monica Bodria, Maddalena Marasa, Elizabeth Raveche, Bruce A. Julian, Anne-Catrin Uhlemann, Krzysztof Kiryluk, Hong Zhang, Vivette D. D'Agati, Simone Sanna-Cherchi, Jan Novak, Ali G. Gharavi
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI186633.
Abstract
BACKGROUND. Hyperinsulinemia and insulin resistance often accompany elevated serum urate levels (hyperuricemia), a highly heritable condition that triggers gout; however, the underlying mechanisms are unclear. METHODS. We evaluated the association between the index of hyperinsulinemia and the fractional excretion of urate (FEUA) in 162 outpatients. The underlying mechanisms were investigated through single-cell data analysis and kinase screening combined with cell culture experiments. In 377,358 participants of the UK Biobank (UKBB), we analyzed serum urate, hyperinsulinemia, and salt intake. We also examined gene-environment interactions using single nucleotide variants in SLC22A12, which encodes urate transporter 1 (URAT1). RESULTS. The index of hyperinsulinemia was inversely associated with FEUA independently of other covariates. Mechanistically, URAT1 cell-surface abundance and urate transport activity were regulated by URAT1-Thr408 phosphorylation, which was stimulated by hyperinsulinemia via AKT. Kinase screening and single-cell data analysis revealed that SGK1, induced by high salt, activated the same pathway, increasing URAT1. Arg405 was essential for these kinases to phosphorylate URAT1-Thr408. In UKBB participants, hyperinsulinemia and high salt intake were independently associated with increased serum urate levels. We found that SLC22A12 eQTL rs475688 synergistically enhanced the positive association between serum urate and hyperinsulinemia. CONCLUSION. URAT1 mediates the association between hyperinsulinemia and hyperuricemia. Our data provide evidence for the role of gene-environment interactions in determining serum urate levels, paving the way for personalized management of hyperuricemia. FUNDING. ACRO Research Grants of Teikyo University; JSPS; the Japanese Society of Gout and Uric & Nucleic Acids; Fuji Yakuhin; Nanken-Kyoten; Medical Research Center Initiative for High Depth Omics.
Authors
Wataru Fujii, Osamu Yamazaki, Daigoro Hirohama, Ken Kaseda, Emiko Kuribayashi-Okuma, Motonori Tsuji, Makoto Hosoyamada, Yuta Kochi, Shigeru Shibata
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI186705.
Abstract
Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induces rapid intravascular neutrophil retention in lung alveolar capillaries without extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote lung inflammation did not require cues from intravascular non-classical monocytes or tissue-resident alveolar macrophages. Instead, lung neutrophil retention depended on neutrophil chemoattractant CXCL2 released by activated classical monocytes. Comparative single-cell RNA-sequencing analysis of direct and remote lung inflammation revealed that alveolar macrophages are highly activated and produce CXCL2 only in direct lung inflammation. Establishing a CXCL2 gradient into the alveolus by intratracheal CXCL2 administration during AKI-induced remote lung inflammation enabled neutrophils to extravasate. We thus discovered important differences in lung neutrophil recruitment in direct versus remote lung inflammation and identified lung capillary neutrophil retention that negatively affects oxygenation by causing a ventilation-perfusion mismatch as a driver of AKI-induced hypoxemia.
Authors
Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M. Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)