Journal of The American Society of Nephrology最新文献

{"title":"Purine Metabolism Regulates the Severity of APOL1 Nephropathy.","authors":"Huihui Huang, Calum Tattersfield, Sonako Jacas, Esilida S Karreci, Aarya Rumde, Jessica Kelly, Lauren Francey, Balajikarthick Subramanian, Ming Huang, Birgitta Ryback, Valerie Schumacher, Seth L Alper, Zsuzsanna K Zsengellér, Martin R Pollak, David J Friedman","doi":"10.1681/ASN.0000001129","DOIUrl":"https://doi.org/10.1681/ASN.0000001129","url":null,"abstract":"<p><strong>Background: </strong>13% of African Americans have a high risk APOL1 genotype, carrying two risk alleles (G1/G1, G1/G2 or G2/G2). The mechanisms underlying nephropathy caused by these APOL1 risk variant genotypes are not fully understood. Downstream of gene function, homeostatic maintenance of a complex and interconnected network of metabolites is essential for normal kidney function. However, this metabolic network can be rerouted by genetic changes or environmental insults, both of which can contribute to development and/or progression of kidney diseases. APOL1 nephropathy exhibits both genetic and environmental triggers, but how APOL1 might alter metabolic homeostasis and how such changes may contribute to disease progression remains unclear.</p><p><strong>Methods: </strong>APOL1 nephropathy was induced in human BAC transgenic APOL1 mice by IFN-γ adenovirus. Non-targeted metabolomics was performed on glomeruli from risk variant (G1/G1 and G2/G2) and non-risk variant (G0/G0) mice as well as on tetracycline-inducible cell lines expressing risk or non-risk variants. Metabolic signaling pathways in risk or non-risk groups were compared and transcriptional changes driving these metabolic differences were identified. Metabolic interventions were performed in both APOL1 risk and non-risk variant-expressing cells and in mice. The effect of metabolic intervention was evaluated by cytotoxicity assays and urine albumin-to-creatinine ratios for cellular and in vivo responses, respectively.</p><p><strong>Results: </strong>Perturbed purine metabolism was the strongest metabolite differentiator between high- and low-risk APOL1 genotypes in cultured cells and in whole glomeruli. Expression of APOL1 G2/G2 downregulated the rate-limiting enzymes of purine biosynthesis and induced ATP depletion. In APOL1 G2/G2-expressing cells, supplementation with the purine biosynthesis precursor AICAr rescued purine biosynthesis, reduced cytotoxicity and boosted ATP. In interferon-γ treated APOL1 G2/G2 transgenic mice, AICAr administration boosted purine biosynthesis, decreased kidney pAMPK, and reduced albuminuria levels. AICAr treatment rescued G2 mouse podocyte death induced by the inflammatory stimuli of combined interferon-γ and Toll-like receptor 1/2 agonist.</p><p><strong>Conclusions: </strong>Increasing purine biosynthesis mitigated APOL1 risk-variant induced injury in cell and transgenic mouse models of APOL1 kidney disease.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microvascular Inflammation in Kidney Transplantation.","authors":"Emmett Tsz Yeung Wong, Robert Balshaw, Ian W Gibson, Julie Ho, Jamie Shaw, Martin Karpinski, Aaron Trachtenberg, Denise Pochinco, Aviva Goldberg, Patricia Birk, Maury Pinsk, David N Rush, Peter W Nickerson, Chris Wiebe","doi":"10.1681/ASN.0000001125","DOIUrl":"https://doi.org/10.1681/ASN.0000001125","url":null,"abstract":"<p><strong>Background: </strong>Microvascular inflammation (sum of glomerulitis (g) and peritubular capillaritis (ptc) scores ≥2) frequently occurs without donor-specific anti-HLA antibodies (DSA), often alongside T-cell-mediated rejection (TCMR), yet its independent prognostic significance remains uncertain.</p><p><strong>Methods: </strong>In a consecutive single-center cohort of 689 kidney transplant recipients (2004-2021), we examined the impact of first g+ptc≥2, TCMR, and de novo DSA (dnDSA) events on death-censored allograft loss using Cox models with time-dependent covariates to account for event timing and overlap.</p><p><strong>Results: </strong>A first g+ptc≥2 occurred in 106/689 (15%) recipients, and 88% had concomitant or sequential TCMR and/or dnDSA. Most g+ptc≥2 biopsies were associated with TCMR (76%), including those with g=0. When assessed individually, the first g+ptc≥2 (HR 4.33, 95%CI 2.5-7.5), TCMR (HR 4.07, 95%CI 2.3-7.1), and dnDSA (HR 4.26, 95%CI 2.2-8.3) events were each associated with death-censored allograft loss. However, in a combined time-dependent model, first TCMR (HR 2.74, 95%CI 1.4-5.4) and dnDSA (HR 2.32, 95%CI 1.1-5.1) remained independently associated with death-censored allograft loss, whereas g+ptc≥2 did not (HR 1.77, 95%CI 0.84-3.73).</p><p><strong>Conclusions: </strong>In a modern tacrolimus-based cohort, g+ptc≥2 without DSA was not associated with worse outcomes after adjustment for serial or concomitant TCMR and dnDSA events.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Pilot Studies When Planning Clinical Trials in Nephrology.","authors":"Ziv Harel, Ivana Prce, Michael Walsh, Ron Wald","doi":"10.1681/ASN.0000001146","DOIUrl":"https://doi.org/10.1681/ASN.0000001146","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gestational Ketosis Compromises Nephron Endowment and Long-Term Kidney Function in Offspring.","authors":"Athar Amleh, Yaniv Makayes, Eden Abergel, Dan Binyamin Varshavsky, Hadar Benyamini, Inbar Plaschkes, Morris Nechama, Oded Volovelsky","doi":"10.1681/ASN.0000001126","DOIUrl":"https://doi.org/10.1681/ASN.0000001126","url":null,"abstract":"<p><strong>Background: </strong>The increasing popularity of ketogenic diets raises concerns regarding their safety during pregnancy. While mild ketosis is a common metabolic adaptation in gestation, the impact of diet-induced, supraphysiological ketosis on fetal kidney development remains unknown. We aimed to investigate the effects of maternal ketosis on offspring nephrogenesis and long-term kidney outcomes.</p><p><strong>Methods: </strong>Two complementary murine models were employed: maternal exposure to a ketogenic diet or β-hydroxybutyrate supplementation throughout gestation. Offspring were evaluated at birth and during postnatal development. Kidney structure and function were assessed by nephron counts, kidney size, and serum markers of kidney function and injury. Nephron progenitor cell (NPC) dynamics were examined using RNA sequencing, gene set enrichment analysis, immunostaining, and qPCR to assess proliferation and inflammation-related markers.</p><p><strong>Results: </strong>Both the ketogenic diet and the β-hydroxybutyrate supplementation models induced maternal ketosis and reduced offspring nephron number. Offspring exhibited impaired kidney function, more pronounced in the ketogenic diet group. Transcriptomic analysis of NPCs revealed downregulation of cell-cycle and Myc signaling pathways, alongside upregulation of inflammatory pathways, including TNFα/NFκB signaling. Immunostaining confirmed reduced NPC proliferation and c-Myc expression, alongside increased TNFα expression. Although postnatal NPC proliferation partially recovered after reversion to a standard diet, it was insufficient to rescue the nephron endowment deficit.</p><p><strong>Conclusions: </strong>Maternal ketosis disrupted nephrogenesis by suppressing c-Myc signaling and activating inflammatory pathways in NPCs, leading to a congenital nephron deficit and compromised adult kidney function.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of Vascular Access-Related Infections in Home Versus In-Center Hemodialysis.","authors":"Brian Bieber, Michael Aragon, Cynthia D'Alessandri-Silva, Kaitlyn Repeck, Eric Weinhandl, Eric Young, Ronald L Pisoni, Jeffrey Perl","doi":"10.1681/ASN.0000001140","DOIUrl":"https://doi.org/10.1681/ASN.0000001140","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping of Phospholipase A2 Receptor Epitopes in Idiopathic Membranous Nephropathy and Clinical Relevance of Epitope Profiles.","authors":"Yanan Liu, Peng Chen, Gang Chen, Junxian Hong, Yangzhong Zhou, Ke Zheng, Sanxi Ai, Zhiying Gao, Peng Xia, Haoyuan Cui, Ruoke Wang, Xuanling Shi, Xuemei Li, Xuewang Li, Linqi Zhang, Yan Qin","doi":"10.1681/ASN.0000000962","DOIUrl":"10.1681/ASN.0000000962","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;Based on the yeast surface display system, we identified three new antigen epitopes of CTLD4, CTLD5, and CTLD6 of phospholipase A2 receptor in membranous nephropathy. In the cohort, 82% of patients showed epitopes beyond Ricin and 56% higher risk for nephrotic syndrome per one more epitope (odds ratio, 1.56; 95% confidence interval, 1.28 to 1.91). Each additional epitope was associated with 15% lower likelihood in clinical remission in this membranous nephropathy cohort (hazard ratio, 0.85; 95% confidence interval, 0.75 to 0.96).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The M-type phospholipase A2 receptor (PLA2R) is the main target antigen of idiopathic membranous nephropathy. Four autoantibody-targeted PLA2R epitope domains, including Ricin, CTLD1, CTLD7, and CTLD8, have been identified. Nevertheless, whether the epitope profile is involved in the progression of PLA2R-associated membranous nephropathy remains controversial. Conventional epitope detection techniques have limitations, and new methods are needed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We constructed a yeast surface-displayed PLA2R antigen library by randomly fragmenting the full-length PLA2R gene and expressing them on the yeast surfaces. Fluorescence-activated cell sorting was performed with sera from PLA2R-related membranous nephropathy patients. Antigenic epitopes were identified through sequencing and clustering. To analyze large-scale samples in batches, we used representative monoclonal yeasts of each structural domain, obtained through the sorting procedure for flow analysis. Clinical and laboratory data were collected at baseline and follow-up. Associations between epitope numbers and disease conditions and prognosis were analyzed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The capacity, diversity, and screening specificity of the PLA2R yeast surface display library were validated. Beyond the reported epitopes, CTLD4, CTLD5, and CTLD6 were newly identified as antigenic targets. In our cohort of 389 idiopathic membranous nephropathy patients, 320 (82%) patients showed epitopes beyond the Ricin domain. The positive rates of CTLD1, CTLD5, and CTLD7 were 53%, 45%, and 54%, respectively, while the detection rates of CTLD6, CTLD8, and CTLD4 were lower at 9%, 8%, and 7%, respectively. The multivariable model demonstrated a 56% higher risk for nephrotic syndrome per epitope increment (odds ratio, 1.56; 95% confidence interval, 1.28 to 1.91) after adjustment for gender, age, disease duration, serum creatinine, and anti-PLA2R titer. Multivariable Cox regression demonstrated that each additional epitope was associated with a 15% lower likelihood in clinical remission (hazard ratio, 0.85; 95% confidence interval, 0.75 to 0.96), with subsequent mediation analysis revealing anti-PLA2R titer accounted for 12% of this effect.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Based on the PLA2R yeast surface display system, we identified three new antigen epitopes of PLA2R in membranous nephropa","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"1043-1056"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of IL-33 in Diabetic Kidney Disease: A Randomized, Placebo-Controlled Phase 2b Trial.","authors":"Alexis Hofherr, Kaisa Mäki-Petäjä, Viknesh Selvarajah, Daniel Grice, Stefano Bartesaghi, Eulalia Jimenez, Roberto Pecoits-Filho, Hiddo J L Heerspink","doi":"10.1681/ASN.0000000966","DOIUrl":"10.1681/ASN.0000000966","url":null,"abstract":"<p><strong>Key points: </strong>In 558 adults with type 2 diabetes and CKD, inhibition of IL-33 by tozorakimab was well tolerated. IL-33 signaling was blocked at all doses, eosinophil counts decreased, and urinary CC-chemokine ligand 2 decreased at the high dose versus placebo. No significant differences in urinary albumin-creatinine ratio were observed between placebo and tozorakimab on top of standard of care.</p><p><strong>Background: </strong>In patients with type 2 diabetes and CKD, elevated inflammatory biomarkers are associated with adverse kidney outcomes. IL-33 contributes to glomerular endothelial inflammation in diabetic kidney disease (DKD). This study evaluated the therapeutic potential of tozorakimab, an IL-33-neutralizing mAb, in DKD.</p><p><strong>Methods: </strong>FRONTIER-1 ( NCT04170543 ) was a phase 2b, randomized, double-blind, placebo-controlled trial including adults with type 2 diabetes, an eGFR of 25-75 ml/min per 1.73 m 2 , urinary albumin-creatinine ratio (UACR) of 100-3000 mg/g, and maximally tolerated renin-angiotensin-aldosterone system blocker therapy. Participants received tozorakimab (30, 60, 120, or 300 mg) or placebo every 28 days for 168 days. All participants received dapagliflozin during days 85-168. The primary end point was UACR change on treatment from baseline to day 169 (per-protocol population). Exploratory end points included inflammatory biomarkers linked to IL-33 activity.</p><p><strong>Results: </strong>Among 558 randomized participants (mean [SD] age 67 [10] years, 30% female, mean [SD] eGFR 48 [15] ml/min per 1.73 m 2 , geometric mean UACR 460 mg/g), tozorakimab ( N =425) was well tolerated with no safety concerns identified. In the per-protocol population ( N =465), IL-33 signaling was inhibited by >95% across all doses, eosinophil counts decreased by >19%, and urinary CC-chemokine ligand 2 levels were significantly decreased by 29% with the 300 mg dose (two-sided 90% confidence intervals, 14% to 42%) versus placebo. However, no statistically significant differences in UACR were observed between placebo (-22%) and treatment (-23% to -25%).</p><p><strong>Conclusions: </strong>Tozorakimab effectively inhibited IL-33 signaling but did not reduce UACR compared with placebo in patients with DKD over 24 weeks.</p><p><strong>Clinical trial registry name and registration number: </strong>ClinicalTrials.gov, NCT04170543.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"1022-1033"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Authors' Reply: Conceptual and Methodological Considerations in Assessing Disparities after Preemptive Kidney Transplant Waitlisting.","authors":"Simeon Adeyemo, Deidra C Crews, Krista L Lentine, Fawaz Al Ammary","doi":"10.1681/ASN.0000000974","DOIUrl":"10.1681/ASN.0000000974","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"1107-1108"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone Mineral Density and the Risk of Fracture According to eGFR in Postmenopausal Women.","authors":"Minsang Kim, Kyungdo Han, Jin Kyung Kwon, Jae-Ik Oh, Jinsun Lee, Jung Hun Koh, Min Woo Kang, Jeong Min Cho, Semin Cho, Seong Geun Kim, Sehyun Jung, Hyuk Huh, Soojin Lee, Eunjeong Kang, Yaerim Kim, Kwon Wook Joo, Dong Ki Kim, Sehoon Park","doi":"10.1681/ASN.0000000960","DOIUrl":"10.1681/ASN.0000000960","url":null,"abstract":"<p><strong>Key points: </strong>Lower bone mineral density was associated with a higher risk of fracture, irrespective of eGFR. At a similar bone mineral density, the fracture risk was higher with lower eGFR, more prominently for hip fractures than for vertebral fractures. The higher risk of fracture associated with lower eGFR was more pronounced in individuals with poor static balance.</p><p><strong>Background: </strong>Although both lower bone mineral density (BMD) and impaired kidney function are well-established risk factors for fracture, large-scale studies evaluating their effects and interaction on fracture, particularly site-specific fractures including vertebra and hip, are still limited.</p><p><strong>Methods: </strong>The main study population included female participants aged 66 years who underwent BMD assessment through dual-energy x-ray absorptiometry through the Korean National Screening Program between 2010 and 2016. BMD was categorized as normal, osteopenia, and osteoporosis on the basis of T -score. Kidney function was classified as eGFR ≥60, 45-59, and <45 ml/min per 1.73 m 2 . Primary outcome was any fracture, including vertebral, hip, and other fractures, defined using International Classification of Diseases, Tenth Revision codes. Subgroup analysis was performed by physical performance, including the single-leg stance test.</p><p><strong>Results: </strong>Among 551,548 participants included in the main study population, 80,514 developed any fracture over a median follow-up of 8.2 (interquartile range, 6.7-10.0) years. The prevalence of osteoporosis was 36%, and those with lower BMD showed higher eGFR and lower body mass index. Lower BMD was associated with a higher risk of any fracture, irrespective of eGFR, with nonsignificant interaction ( P for interaction = 0.54). Among participants with normal BMD, those with eGFR <45 ml/min per 1.73 m 2 showed a greater risk of hip fracture than those with normal eGFR (adjusted hazard ratio, 2.44 [1.88-3.18]), whereas vertebral fracture risks were similar across different eGFR categories at a given BMD status. Furthermore, a higher fracture risk with lower eGFR was more pronounced in women with poor static balance assessed by the single-leg stance test than in those with normal static balance.</p><p><strong>Conclusions: </strong>In postmenopausal women, lower BMD was associated with a higher fracture risk, irrespective of eGFR. However, at any given BMD, lower eGFR was associated with a greater risk for hip fracture, but not for vertebral fracture.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"984-994"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Ciliary Phosphoinositide Pathway Regulates the Dosage of Polycystins in Primary Cilia.","authors":"Chuan Chen, Zhifei Wang, Yue Gao, Madilyn R Ellis, Biyun Ji, Cynthia J Sieben, Courtney J Haycraft, Mandy Croyle, Ariana Aghevli, Qingwen Xu, Jielu H Robichaud, Kai He, Chunhua Chen, Yan Huang, Bradley K Yoder, Jinghua Hu, Peter C Harris, Yong Yu, Kun Ling","doi":"10.1681/ASN.0000000942","DOIUrl":"10.1681/ASN.0000000942","url":null,"abstract":"<p><strong>Key points: </strong>Inositol polyphosphate-5-phosphatase E (INPP5E) and type Ig phosphatidylinositol-4-phosphate 5-kinase (PIPKIγ) coordinated the homeostasis of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate in primary cilia. Modulating INPP5E or PIPKIγ activity changed the level of polycystin-1 and polycystin-2 in primary cilia. INPP5E inhibition increased the hypomorphic PKD1 variants (PC1-R3277C) in cilia and reduced cystogenesis in the kidney in vitro .</p><p><strong>Background: </strong>Autosomal dominant polycystic kidney disease is mainly caused by mutations in PKD1 and PKD2 , which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 assemble a cation channel complex enriched in primary cilium, a sensory organelle associated with various developmental diseases, including polycystic kidney disease (PKD). Accumulating evidence supports the necessity of functional polycystin (PC) complex in cilia to prevent cystogenesis in the kidney, indicating that improving their ciliary levels may ameliorate defects underlying PKD pathogenesis. Yet, molecular mechanisms underlying the ciliary targeting and homeostasis of the PC complex are not fully understood.</p><p><strong>Methods: </strong>Indirect immunofluorescence microscopy was used to monitor ciliary levels of PC1 and PC2 in renal epithelial cells. Electrophysiology analysis in oocytes was used to determine the channel activity of the PC complex. Cystogenesis in the kidney was measured using in vitro 3D-Matrigel cell models and ex vivo mouse embryonic kidney models.</p><p><strong>Results: </strong>Suppressing inositol polyphosphate-5-phosphatase E (INPP5E) or activating type Ig phosphatidylinositol-4-phosphate 5-kinase raised ciliary levels of the PC complex in both normal renal epithelial cells and cells carrying autosomal dominant polycystic kidney disease mutations that interrupt the trafficking of PCs into cilia, including GANAB inactivation and the trafficking PKD1 mutation p.Arg3277Cys (RC). PC1 RC formed a complex with PC2 and exhibited normal channel activity in vitro . An INPP5E that increases PC1 and PC2 in cilia, suppressed in vitro forskolin-induced cystogenesis of inner medullary collecting duct epithelial cell line 3 cells in 3D Matrigel and ex vivo cyst formation in embryonic Pkd1RC/RC mouse kidneys.</p><p><strong>Conclusions: </strong>Our results demonstrated that increasing the ciliary level of PCs, by manipulating a ciliary phosphoinositide signaling axis, enhanced the functionality of PCs and suppressed cystogenesis of renal epithelial cells in vitro .</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"944-958"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13101048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}