Nephrology
Abstract
Fibrosis is the final common pathway leading to end stage chronic kidney disease (CKD). However, the function of protein palmitoylation in renal fibrosis and underlying mechanisms remain unclear. In this study, we observed that the expression of the palmitoyltransferase ZDHHC18 was significantly elevated in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models, and was significantly upregulated in the fibrotic kidneys of chronic kidney disease patients. Functionally, tubule-specific deletion of ZDHHC18 attenuated tubular epithelial cells partial epithelial-to-mesenchymal transition (EMT), then reduced production of profibrotic cytokine and alleviates tubulointerstitial fibrosis. In contrast, ZDHHC18 overexpression exacerbated progressive renal fibrosis. Mechanistically, ZDHHC18 catalyzed the palmitoylation of HRAS, which is pivotal for its translocation to the plasma membrane and subsequent activation. HRAS palmitoylation promoted downstream phosphorylation of MEK/ERK and further activated RREB1, enhancing SMAD binding to the Snai1 cis-regulatory regions. Taken together, our findings suggest that ZDHHC18 plays a crucial role in renal fibrogenesis and presents a potential therapeutic target for combating kidney fibrosis.
Authors
Di Lu, Gulibositan Aji, Guanyu Li, yue li, Wenlin Fang, Shuai Zhang, ruiqi yu, Sheng Jiang, xia gao, Yuhang Jiang, Qi Wang
Abstract
The role of macrophages remains incompletely understood in kidney injury and repair. Their plasticity offers an opportunity to polarize them towards mediating injury resolution in both native and transplanted kidneys undergoing ischemia and/or rejection. Here, we show that infiltrating kidney macrophages augmented their AIF-1 expression after injury. Aif1 genetic deletion led to macrophage polarization towards a reparative phenotype while halting the development of kidney fibrosis. The enhanced repair was mediated by higher levels of anti-inflammatory and pro-regenerative markers leading to a reduction in cell death and increase in proliferation of kidney tubular epithelial cells following ischemic reperfusion injury. Adoptive transfer of Aif1-/- macrophages to Aif1+/+ mice conferred protection against ischemia reperfusion injury. Conversely, depletion of macrophages reversed the tissue-reparative effects in Aif1-/- mice. We further demonstrated an increased expression of AIF-1 in human kidney biopsies from native kidneys with acute kidney injury or chronic kidney disease, as well as in biopsies from kidney allografts undergoing acute or chronic rejection. We conclude that AIF-1 is a macrophage marker of renal inflammation, and its targeting uncouples macrophage reparative functions from profibrotic functions. Thus, therapies inhibiting AIF-1 when ischemic injury is inevitable have the potential to reduce the global burden of kidney disease.
Authors
Irma Husain, Holly Shah, Collin Z. Jordan, Naveen R. Natesh, Olivia K. Fay, Yanting Chen, Jamie R. Privratsky, Hiroki Kitai, Tomokazu Souma, Shyni Varghese, David N. Howell, Edward B. Thorp, Xunrong Luo
Abstract
Authors
Felicitas E. Hengel, Silke Dehde, Oliver Kretz, Jonas Engesser, Tom Zimmermann, Tobias B. Huber, Nicola M. Tomas
Abstract
Vitamin D regulates mineral homeostasis. The most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is synthesized by CYP27B1 from 25-dihydroxyvitamin D (25D) and inactivated by CYP24A1. Human monogenic diseases and genome-wide association studies support a critical role for CYP24A1 in regulation of mineral homeostasis, but little is known about its tissue-specific effects. Here, we describe the responses of mice with inducible global deletion, kidney-specific, and intestine-specific deletion of Cyp24a1 to dietary calcium challenge and chronic kidney disease (CKD). Global and kidney-specific Cyp24a1 deletion caused similar syndromes of systemic vitamin D intoxication: elevated circulating 1,25D, 25D and fibroblast growth factor 23 (FGF23), activation of vitamin D target genes in the kidney and intestine, hypercalcemia, and suppressed parathyroid hormone (PTH). In contrast, mice with intestine-specific Cyp24a1 deletion demonstrated activation of vitamin D target genes exclusively in the intestine despite no changes in systemic vitamin D levels. In response to a high calcium diet, PTH was suppressed despite normal serum calcium. In mice with CKD, intestinal Cyp24a1 deletion decreased PTH and FGF23 without precipitating hypercalcemia. These results implicate kidney CYP24A1 in systemic vitamin D regulation while independent local effects of intestinal CYP24A1 could be targeted to treat secondary hyperparathyroidism in CKD.
Authors
Michaela A.A. Fuchs, Alexander Grabner, Melody Shi, Susan L. Murray, Emily J. Burke, Nejla Latic, Venkataramana Thiriveedi, Jatin Roper, Shintaro Ide, Koki Abe, Hiroki Kitai, Tomokazu Souma, Myles Wolf
Abstract
The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain–containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.
Authors
Silvana Bazua-Valenti, Matthew R. Brown, Jason Zavras, Magdalena Riedl Khursigara, Elizabeth Grinkevich, Eriene-Heidi Sidhom, Keith H. Keller, Matthew Racette, Moran Dvela-Levitt, Catarina Quintanova, Hasan Demirci, Sebastian Sewerin, Alissa C. Goss, John Lin, Hyery Yoo, Alvaro S. Vaca Jacome, Malvina Papanastasiou, Namrata Udeshi, Steven A. Carr, Nina Himmerkus, Markus Bleich, Kerim Mutig, Sebastian Bachmann, Jan Halbritter, Stanislav Kmoch, Martina Živná, Kendrah Kidd, Anthony J. Bleyer, Astrid Weins, Seth L. Alper, Jillian L. Shaw, Maria Kost-Alimova, Juan Lorenzo B. Pablo, Anna Greka
Abstract
Authors
Mark Elliott, Krzysztof Kiryluk, Ali Gharavi
Abstract
Authors
Xiaona Wang, Dongyan Wang
Abstract
Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1-3 in regulating post-ischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the three PHD isoforms in both mice and humans. Post-ischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. Single-cell RNA-seq analysis of the post-ischemic endothelial PHD1, PHD2 and PHD3 deficient (PHDTiEC) kidney revealed an endothelial hypoxia and glycolysis related gene signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed pro-inflammatory EC activation reducing monocyte-endothelial cell interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.
Authors
Ratnakar Tiwari, Rajni Sharma, Ganeshkumar Rajendran, Gabriella S. Borkowski, Si Young An, Michael Schonfeld, James O'Sullivan, Matthew J. Schipma, Yalu Zhou, Guillaume Courbon, Benjamin R. Thomson, Valentin David, Susan E. Quaggin, Edward B. Thorp, Navdeep S. Chandel, Pinelopi P. Kapitsinou
Abstract
Fibrosis represents the uncontrolled replacement of parenchymal tissue with extracellular matrix (ECM) produced by myofibroblasts. While genetic fate-tracing and single-cell RNA-Seq technologies have helped elucidate fibroblast heterogeneity and ontogeny beyond fibroblast to myofibroblast differentiation, newly identified fibroblast populations remain ill defined, with respect to both the molecular cues driving their differentiation and their subsequent role in fibrosis. Using an unbiased approach, we identified the metalloprotease ADAMTS12 as a fibroblast-specific gene that is strongly upregulated during active fibrogenesis in humans and mice. Functional in vivo KO studies in mice confirmed that Adamts12 was critical during fibrogenesis in both heart and kidney. Mechanistically, using a combination of spatial transcriptomics and expression of catalytically active or inactive ADAMTS12, we demonstrated that the active protease of ADAMTS12 shaped ECM composition and cleaved hemicentin 1 (HMCN1) to enable the activation and migration of a distinct injury-responsive fibroblast subset defined by aberrant high JAK/STAT signaling.
Authors
Konrad Hoeft, Lars Koch, Susanne Ziegler, Ling Zhang, Steffen Luetke, Maria C. Tanzer, Debashish Mohanta, David Schumacher, Felix Schreibing, Qingqing Long, Hyojin Kim, Barbara M. Klinkhammer, Carla Schikarski, Sidrah Maryam, Mathijs Baens, Juliane Hermann, Sarah Krieg, Fabian Peisker, Laura De Laporte, Gideon J.L. Schaefer, Sylvia Menzel, Joachim Jankowski, Benjamin D. Humphreys, Adam Wahida, Rebekka K. Schneider, Matthias Versele, Peter Boor, Matthias Mann, Gerhard Sengle, Sikander Hayat, Rafael Kramann
Abstract
BACKGROUND It is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODS Three cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTS Monogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (–3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (–2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONS Monogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATION NA.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.
Authors
Mark D. Elliott, Natalie Vena, Maddalena Marasa, Enrico Cocchi, Shiraz Bheda, Kelsie Bogyo, Ning Shang, Francesca Zanoni, Miguel Verbitsky, Chen Wang, Victoria Kolupaeva, Gina Jin, Maayan Sofer, Rafael Gras Pena, Pietro A. Canetta, Andrew S. Bomback, Lisa M. Guay-Woodford, Jean Hou, Brenda W. Gillespie, Bruce M. Robinson, Jon B. Klein, Michelle N. Rheault, William E. Smoyer, Larry A. Greenbaum, Larry B. Holzman, Ronald J. Falk, Afshin Parsa, Simone Sanna-Cherchi, Laura H. Mariani, Matthias Kretzler, Krzysztof Kiryluk, Ali G. Gharavi, CureGN Consortium
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)