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A novel antidiuretic hormone governs tumour-induced renal dysfunction

Nature volume 624, pages 425–432 (2023)Cite this article

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Abstract

Maintenance of renal function and fluid transport are essential for vertebrates and invertebrates to adapt to physiological and pathological challenges. Human patients with malignant tumours frequently develop detrimental renal dysfunction and oliguria, and previous studies suggest the involvement of chemotherapeutic toxicity and tumour-associated inflammation1,2. However, how tumours might directly modulate renal functions remains largely unclear. Here, using conserved tumour models in Drosophila melanogaster3, we characterized isoform F of ion transport peptide (ITPF) as a fly antidiuretic hormone that is secreted by a subset of yki3SA gut tumour cells, impairs renal function and causes severe abdomen bloating and fluid accumulation. Mechanistically, tumour-derived ITPF targets the G-protein-coupled receptor TkR99D in stellate cells of Malpighian tubules—an excretory organ that is equivalent to renal tubules4—to activate nitric oxide synthase–cGMP signalling and inhibit fluid excretion. We further uncovered antidiuretic functions of mammalian neurokinin 3 receptor (NK3R), the homologue of fly TkR99D, as pharmaceutical blockade of NK3R efficiently alleviates renal tubular dysfunction in mice bearing different malignant tumours. Together, our results demonstrate a novel antidiuretic pathway mediating tumour–renal crosstalk across species and offer therapeutic opportunities for the treatment of cancer-associated renal dysfunction.

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Fig. 1: Tumour-derived ITP causes bloating and hyperglycaemia.
Fig. 2: ITPF mediates tumour-induced fluid accumulation and trehalose increase.
Fig. 3: ITPF activates NOS–cGMP signalling in stellate cells to impair renal excretion.
Fig. 4: Tumour-derived ITPF signals via TkR99D in stellate cells.
Fig. 5: NK3R inhibition mitigates renal injury in tumour-bearing mice.

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Data availability

RNA-seq data of adult midgut were deposited in the Gene Expression Omnibus (GEO) under accession GSE113728. RNA-seq data of adult Malpighian tubules were deposited in the Gene Expression Omnibus under accession GSE240166. FlyBase genome annotation version r6.39 was used for mapping of RNA-seq data. Any additional information required to reanalyse the data reported in this paper is available from the corresponding author upon request. Source data are provided with this paper.

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Acknowledgements

We thank the TRiP at Harvard Medical School, Bloomington Drosophila Stock Center and NIG in Japan for providing fly stocks; M. Tatar for c724-GAL4 flies; P. Kapahi for c710-GAL4 and c42-GAL4 flies; G. Juhász for esg-GAL4, UAS-mCherry-CD8, tub-GAL80TS flies; X. Ma for Tester40A (ey-Flp; tub-Gal80, FRT40A; Act > y+>Gal4, UAS-GFP) and Lgl−/− FRT40A, UAS-RasV12 flies; F. Guo for nSyb-GAL4 flies; W. Zhang for GMR-LexA flies; N. Perrimon for pros-Gal4, UAS-Ras1A and UAS-RafF179 flies; Tsinghua University Fly Center and Shanghai Core Facility of Drosophila Resource and Technology for generation of ITP shRNAi and transgenic flies; N. Perrimon and J. Yao for technical support; and X. Feng, Y. Liu, B. Song and H. Shu for insightful comments. Work in the Song laboratory was supported by the Chinese Ministry of Science and Technology (National Key R&D Program, 2021YFC2700700), Chinese National Natural Science Foundation (91957118, 31800999 and 31971079) and the Fundamental Research Funds for the Central Universities (2042022dx0003). Work in the Ye laboratory was supported by Chinese Ministry of Science and Technology (National Key R&D Program, 2018YFC2002300).

Author information

Author notes

  1. These authors contributed equally: Wenhao Xu, Gerui Li

Authors and Affiliations

  1. Department of Geriatrics, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, Hubei, China

    Wenhao Xu, Gerui Li, Yuan Chen, Xujun Ye & Wei Song

  2. Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China

    Wenhao Xu, Yuan Chen & Wei Song

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  1. Wenhao Xu
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Contributions

W.X. designed and performed experiments, including metabolic assays, qPCR, genetic manipulation and generation of transgenic flies. W.X. and G.L. performed mouse experiments. Y.C. validated yki3SA-tumour-bearing flies using the LexA/LexAop system. W.S. designed the study. X.Y. and W.S. discussed results and wrote the manuscript.

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Correspondence to Xujun Ye or Wei Song.

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Extended data figures and tables

Extended Data Fig. 1 ITP is essential for tumor-induced fluid accumulation.

(a-b) Abdomen bloating and tumor growth (a) and wasting effects (b), including bloating rates (n = 3, 20 flies/replicate) and whole-body levels of trehalose and TAG (n = 3, 5 flies/replicate) of flies bearing yki3SA tumors plus ITP knockdown using another RNAi line (JF, JF01817) at 29 °C for 8 days. (c-d) Electronic microscopy analysis showing myofiber dysintegrity (gaps between myofibers and mitochondria as indicated by arrow heads) in indicated flies with tumor induction at 29 °C for 8 days. (e-f) Abdomen (e) and water/dry mass ratio (n = 3, 10 flies/replicate) of control flies bearing ITP RNAi in ISCs for 8 days. (g-i) Gut gene expression levels (g, n = 3, 10 flies/replicate) and water/dry mass ratio (h, left, n = 3, 8 flies/replicate), and ITP-cell distribution in the gut (i, ITP>mCherry) of flies bearing LexA-yki3SA tumors at 29 °C for 4 days (magenta, anti-pros antibody; red, ITP>mCherry; green, esg-LexATS > GFP). (j) Abdomen bloating (upper) and gut tumors (lower) of flies bearing LexA-yki3SA-gut tumors and pros-GAL4-induced ITP RNAi in the gut at 29 °C for 4 days. (k-x) Abdomen with bloating (k, o, upper) and without bloating (s, v, upper), tumors (lower, k, gut; o, eye disc; s, eye; v, non-tumor), water/dry mass ratios (l, t, w, n = 3, 10 flies/replicate; p, n = 3, 10 larvae/replicate;), as well as tumor gene expression (m, gut, n = 3, 10 flies/replicate; q, disc+brain, n = 3, 10 larvae/replicate; u, x, head, n = 3, 10 flies/replicate), of indicated adult flies or larvae. (k-m) Adult flies bearing NDN,RasV12-gut tumors (esgTS > NDN,RasV12) with ITP RNAi (v43848) in at 27 °C for 6 days. (o-q) 3rd instar larvae bearing lgl-/-,RasV12-disc tumors (eyFLP; tub-Gal80, FRT40A/Lgl-, FRT40A, UAS-RasV12; Act > y+>Gal4, UAS-GFP/+) with ITP RNAi (v43848) in at 25 °C for 7 days. (r) ITP (lower, ITP > GFP) is not expressed in the eye-disc clones (upper, eyFLP; tub-Gal80, FRT40A/FRT40A; Act > y+>Gal4, UAS-GFP/+) of 3rd-instar larvae. (s-u) Adult flies bearing yki3SA-eye tumors (GMR-LexA>yki3SA) at 25 °C for 8 days. (v-x) Adult flies with yki3SA overexpression in the pan-neurons (nSybTS > GFP,yki3SA) at 29 °C for 13 days. A representative result of three independent experiments is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test (f, g, h, m, t, u, w, x) and one-way ANOVA with Bonferroni’s multiple-comparisons test (b, l, p, q).

Source Data

Extended Data Fig. 2 ITPF, but not ITPC or ITPE, causes fluid accumulation in both normal and tumor-bearing flies.

Abdomen with (a, c, e, h, k, upper) or without bloating (p, r, u, w, y, upper), guts with (a, c, lower) or without tumors (r, y, lower), bloating rates (i, n = 3, 20 flies/replicate) and energy reserves (b, f, i, l, s, n = 3, 5 flies/replicate), and water/dry mass ratios (d, g, j, m, o, q, t, v, x, z, n = 3, 10 flies/replicate; o, n = 3, 5 larvae/replicate) of indicated adult flies or 3rd instar larvae. (a-b) Adult files bearing Ras1A-gut tumors with ITP overexpression at 29 °C for 8 days. (c-d) Adult files bearing RafF179-gut tumors with ITPF overexpression at 29 °C for 6 days. (e-m) Adult flies with tissue-specific ITP overexpression. Fat body, CgTS at 29 °C for 6 days (e-g) and Bsg-LexATS at 29 °C for 4 days (h-j). Muscle, MhcTS at 29 °C for 2 days (k-m). (n-o) Expression strategy (n, left) for 3rd-instar larvae with ITPF overexpression in the fat body at 29 °C for 2 days. (p-q) Adult flies with fat-body overexpression of other tumor-secreted proteins (ImpL2, Pvf1, and Upd3) at 29 °C for 6 days. (r-z) Adult flies with ITP overexpression in the enterocytes (ECs) (r-t, Myo1ATS >, 12 days), ITP-producing cells (u-v, ITPTS >, 10 days), EECs (w-x, prosTS >, 10 days), or ISCs (y-z, esgTS >, 10 days) at 29 °C. A representative result of three independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test (d, i, j, o, x, z) and one-way ANOVA with Bonferroni’s multiple-comparisons test (b, f, g, l, m, q, s, t, v).

Source Data

Extended Data Fig. 3 ITPF activates cGMP signaling in MTs to cause fluid accumulation.

(a) Excretion of gut contents (left, flies were fed blue-dye containing food for 24 h prior to 1 h excretion of gut contents in the EP tubes; right, quantification of blue dye in feces, n = 3, 30 flies/replicate) from feces of flies bearing yki3SA-tumor and ITP RNAi at 29 °C for 8 days. (b-e) PCA analysis of gene expression (b) and heatmap showing expression levels of NF-κB/IMD signaling target genes (e) in MTs of indicated flies with tumor induction (esgTS>yki3SA,ITP-i-v) for 8 days. (c-d) Gene Ontology Enrichment analysis of ITP-dependent differential gene expression indicating that the following terms of Biological Process (c) and Cellular Compartment (d) are significantly enriched. (f) Model of cpGFP-based FlincG2 biosensor with sensory domains capable of cGMP binding to indicate intracellular cGMP level. The diagram was created using PowerPoint. (g-k) Images (g-i) and quantification (j-k) of dissected MTs that were treated with ITPF (100 nM), 8-Br-cGMP (1 mM), L-NAME (1 mM) from 10d-old adult flies overexpressing reporter for second messengers (g, j, tub>FlincG2; h, upper, tub>Epac1-Camps; h, lower, tub > GCaMP6; i, k, c42>FlincG2, n = 3). (h) Images of dissected MTs that were treated with ITPF from 10d-old adult flies globally overexpressing Epac1-Camps and GCaMP6 (tub >) for monitoring cAMP and Ca2+, respectively. (i) Images of dissected MTs that were treated with ITPF (100 nM) for 15 min from 10d-old adult flies overexpressing FlincG2 in the PCs (c42 >). (l) Single-nuclear RNAseq analysis of gene expression, including soluble Gycs (Gyc88E, Gyc89Da, Gyc89Db, Gycα99B, Gycβ100B), Nos, cGMP-induced kinases (for, Pkg21D), in PCs (DH-31R) or SCs (LkR) of adult MTs (https://scope.aertslab.org/#/FlyCellAtlas/FlyCellAtlas%2Fs_fca_biohub_malpighian_tubule_10x.loom/gene). (m-p) Abdomen bloating (m, o) and water/dry mass ratios (n, p, n = 3, 10 flies/replicate) of adult flies with ITPF overexpression (Bsg-LexATS > ITPF) and simultaneous RNAi in the SCs (m-n, c724 >; o-p, LkR >) at 29 °C for 4 days. A representative result of three independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test (n, left, middle, p) and one-way ANOVA with Bonferroni’s multiple-comparisons test (a, n, right).

Source Data

Extended Data Fig. 4 SC TkR99D responds to ITPF to impair renal functions.

(a) Expression pattern of 256 GPCRs in different cell types of renal system using snRNAseq analysis (https://www.flyrnai.org/scRNA/kidney). 6 GPCRs that are specifically expressed in SCs, but not PCs, are indicated as red. (b) GFP expression driven by TkR99D-GAL4 and other established GAL4 lines targeting SCs (c710-, c724-, LkR-GAL4) in 6d-old adult MTs. (c-m) Abdomen bloating (c, e, g, j, l), bloating rates (d, left, n = 3, 20 flies/replicate), whole-body energy reserves (d, right, n = 3, 5 flies/replicate), water/dry mass ratios (f, k, m, n = 3, 10 flies/replicate) of adult flies with ITPF overexpression in the fat body (Bsg-LexATS > ITPF) and simultaneous TkR99D RNAi in the SCs of MTs (c-d, c710 >; e-f, LkR >; g, c724 >), muscle (j-k, Mhc >) or fat body (l-m, R4 >) at 29 °C for 4 days. (h-i) Abdomen (h) and water/dry mass ratios (i, n = 3, 10 flies/replicate) of control adult flies with TkR99D RNAi in the SCs at 29 °C for 8 days. (n) Quantification of dissected MTs with FincG2 expression in SCs that were treated with ITPF (100 nM) plus different doses of Tk-1 (M) from 10d-old adult flies (n = 3, >15 SCs/MT). (o-r) Abdomen bloating (o, q) and water/dry mass ratios (p, r, n = 3, 10 flies/replicate) of adult flies with ITPF overexpression in the fat body and simultaneous activation of Tk-EECs in the gut (o-p, Bsg-LexATS > ITPF // Tk-g>TrpA1), or control flies without ITPF expression but bearing activation or ablation (q-r, Tk-gTS>TrpA1 or Rpr) of Tk-EECs in the gut, at 29 °C for 4 days. (s-t) Abdomen bloating and tumor growth (s) and water/dry mass ratios (t, n = 3, 10 flies/replicate) of indicated flies with LexA-tumor induction in midgut and GAL4-induced TkR99D RNAi in renal SCs (left, c724 >; right, LkR >) at 29 °C for 4 days. A representative result of three independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test (d, f, i, k, m, p, t) and one-way ANOVA with Bonferroni’s multiple-comparisons test (r).

Source Data

Extended Data Fig. 5 Antagonist targeting human NK3R diminishes ITPF-induced renal dysfunction.

(a) Expression patterns of genes encoding NK1R/2 R/3 R in human (Human Protein Atlas) (TACR1/NK1R: https://v20.proteinatlas.org/ENSG00000115353-TACR1/tissue; TACR2/NK2R: https://v20.proteinatlas.org/ENSG00000075073-TACR2/tissue; TACR3/NK3R: https://v20.proteinatlas.org/ENSG00000169836-TACR3/tissue). (b) Quantification of dissected MTs that were treated with ITPF (100 nM) plus Fezolinetant (F, 200 μM) or Pavinetant (P, 200 μM) from 10d-old adult flies overexpressing FlincG2 in the SCs (n = 3, >15 SCs/MT). (c) cGMP levels in HEK-293T cells that were transiently transfected to express fly TkR99D for 48 h and treated with ITPF (100 nM) plus Fezolinetant (F, 200 μM) or Pavinetant (P, 200 μM) for 15 min were detected using ELISA kits (n = 3). (d-j) Abdomen bloating and tumor growth (d, e, h), whole-body levels of trehalose and TAG (f, i, n = 3, 5 flies/replicate), and bloating rates (g, j, 30 flies in a pool) of indicated inhibitor-feeding flies (μM in the food) with simultaneous yki3SA-gut tumor induction (d-g, esgTS>yki3SA, 8 days) or ITPF overexpression (h-j, CgTS > ITPF, 6 days) at 29 °C. A representative result of three independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test and one-way ANOVA with Bonferroni’s multiple-comparisons test (c, f, i).

Source Data

Extended Data Fig. 6 Pharmaceutical NK3R inhibition did not affect energy wasting or renal inflammation in ApcMin/+ mice.

(a, i) Intervention strategy. The diagram was created using Adobe Illustrator. (b-o) Body weight changes (b, j), daily drinking and urine volumes (c, n = 3, pooled; l, n = 5), kidney weights (d, k), circulating factors in the blood like albumin (ALB), arginine vasopressin (AVP), creatinine and TAG, ALB (e, m) and β2-MG in the urine (f), and renal morphologies (HE staining) and pathologies like fibrosis (Masson’s Trichrome staining, NGAL and KIM-1 expression) (g, n), as well as gene expression in the kidney or brain (h, o) of male ApcMin/+ mice treated with NK3R inhibitors. (a-h) 21-week-old male ApcMin/+ mice that were IP injected 50 mg/Kg/day Pavinetant (P50) for 8 days (n = 7). (i-o) 16-17-week-old male ApcMin/+ mice that were IP injected 10 mg/Kg/day Fezolinetant (F10) for 7 days (n = 6). A representative result of three independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test and one-way ANOVA with Bonferroni’s multiple-comparisons test (c-f, h, k-m, o).

Source Data

Extended Data Fig. 7 IP injection of NK3R inhibitors or agonist hardly affected renal functions in control mice.

(a) Cumulative (left) and end-point (right) urine excretion during 6 h after an acute 1 mL water load by gavage in 8-week-old male C57BL/6 mice after IP injection of 50 mg/Kg/day Pavinetant (P50) for 7 days (pooled, n = 4). (b-d) Daily urine and water intake volumes (b, n = 7), kidney weights (c), blood factors like glucose, ALB, AVP, creatinine, urea nitrogen (BUN) (d), urine factors like ALB and β2-MG (e, n = 5), renal morphologies (HE staining) and pathologies like brush-border loss (PAS staining) (f), as well as and gene expression in the kidney (g) of control 8-week old male C57BL/6 mice received IP injection of 10 mg/Kg/day Fezolinetant (F10) or 50 mg/Kg/day Pavinetant (P50) for 7 days (n = 7). (h-t) Body weight changes (h, o), daily urine volumes (i, n = 5; p, n = 4, pooled), blood glucose (j, q), kidney weights (k, r), kidney injury like dilatation and intracellular vacuolization (l, s, H&E staining), as well as gene expression in the kidney or brain (m, t), of C57BL/6 mice treated with NKB. (n) Intervention strategy. The diagram was created using Adobe Illustrator. Control 8-week-old male C57BL/6 mice (n = 7) or 16-17-week old male ApcMin/+ mice were IP injected NKB (0.02 or 0.1 mg/Kg/day) for 8 days (n = 6). A representative result of two independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test (a, right) and one-way ANOVA with Bonferroni’s multiple-comparisons test (b-e, g, i-k, m, p-r, t).

Source Data

Extended Data Fig. 8 Pharmaceutical NK3R inhibition alleviated renal injury in mice bearing ipMFC and ipHCT gastric tumors.

(a, l) Intervention strategy. The diagram was created using Adobe Illustrator. (b-t) Body weight changes (b, m), renal NK3R protein levels (c, left, anti-NK3R, Ab124025; right, NBP3-06055), actual tumor weights (d, n), daily drinking volumes (e), kidney weights (f, o), cumulative urine excretion after an acute water load by gavage (g, 1 mL; r, 0.8 mL; pooled, n = 3), blood factors like glucose, TAG, ALB, AVP, blood creatinine (h, p), urine factor like ALB and β2-MG (i, q), renal morphologies (HE staining) and pathologies like fibrosis (Masson’s Trichrome staining; NGAL and KIM-1 expression) (j, s), as well as gene expression in the kidney and brain (k, t), of indicated mice with inhibitor administration. (a-k) 7-week-old male C57BL/6 mice that were IP injected 50 mg/Kg/day Pavinetant (P50) for 7 days after growth of IP injected MFC tumor cells for 5 days (n = 6). (l-t) 8-week-old male NSG mice that were IP injected 50 mg/Kg/day Pavinetant (P50) for 8 days after growth of IP injected HCT116 colon tumor cells for 11 days (n = 7). A representative result of two independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test (d, n) and one-way ANOVA with Bonferroni’s multiple-comparisons test (e, f, h, i, k, o-q, t).

Source Data

Extended Data Fig. 9 Pharmaceutical NK3R inhibition alleviated renal injury in mice bearing patient-derived xenografts (PDX-w) and scLLC lung tumors.

(a, j) Intervention strategy. The diagram was created using Adobe Illustrator. (b-u) Body weight changes (b, k), estimated tumor weights (c, l), daily drinking and urine volumes (d, pooled, n = 4; n, n = 5), kidney weights (e, o), blood factors like glucose, ALB, AVP, creatinine and BUN (f, p), urine factors like ALB and urine β2-MG (g, q), urine excretion after an acute 1 mL water load by gavage (r, pooled, n = 3), renal morphologies (HE staining) and pathologies (fibrosis, Masson’s Trichrome staining; dilatation and brush-border loss, PAS staining; NGAL and KIM-1 expression) (h, s, n = 6, t), as well as gene expression in the kidney and brain (i, u), of indicated mice with inhibitor administration. (a-i) Female 8-week-old NCG mice that were IP injected 50 mg/Kg/day Pavinetant (P50) for 7 days after growth of subcutaneously implanted gastric PDX-w for 45 days (n = 8). (j-u) Male 7-week-old C57BL/6 mice that were IP injected 50 mg/Kg/day Pavinetant (P50) for 6 days after growth of SC injected LLC lung tumor cells for 16 days (n = 6). A representative result of two independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test (c) and one-way ANOVA with Bonferroni’s multiple-comparisons test (d-g, i, n-q, s, u).

Source Data

Extended Data Fig. 10 Pharmaceutical NK3R inhibition alleviated renal injury in mice bearing scHCT116 colon and scB16 melanoma tumors.

(a, k) Intervention strategy. The diagram was created using Adobe Illustrator. (b-t) Body weight changes (b, l), estimated tumor weights (c, m), daily urine volumes (d, n = 5; n, pooled, n = 4), kidney weights (e, o), blood factors like glucose, ALB, AVP, creatinine and BUN (f, p), urine factor ALB and urine β2-MG (g, q), renal tubular injury including dilatation, intracellular vacuolization and brush-border loss (h, r, HE and PAS staining) and the quantification (i, n = 7; s, n = 6, according to PAS staining), as well as gene expression in the kidney and brain (j, t), of indicated mice with inhibitor administration. (a-j) Female 8-week-old NSG mice that were IP injected 10 mg/Kg/day Fezolinetant or 50 mg/Kg/day Pavinetant (P50) for 8 days after growth of SC injected HCT116 colon tumor cells for 20 days (n = 7). (k-t) Male 8-week-old C57BL/6 mice that were IP injected 50 mg/Kg/day Pavinetant (P50) for 5 days after growth of SC injected B16 tumor cells for 10 days (n = 6). A representative result of two independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test and one-way ANOVA with Bonferroni’s multiple-comparisons test (d-g, i, j, n-q, s, t).

Source Data

Extended Data Fig. 11 Pharmaceutical NK3R inhibition alleviated renal injury in mice bearing patient-derived xenografts (PDX-n and PDX-r).

(a, k) Intervention strategy. The diagram was created using Adobe Illustrator. (b-t) Body weight changes (b, l), estimated tumor weights (c, m), daily urine and drinking volumes (pooled, d, n = 4; n, n = 4), kidney weights (e, o), blood factors like glucose, TAG, ALB, AVP and creatinine (f, p), urine ALB and urine β2-MG (g, q), renal tubular injury including dilatation, intracellular vacuolization and brush-border loss (h, r, HE and PAS staining) and the quantification (i, n = 6; s, n = 6; according to PAS staining), as well as gene expression in the kidney and brain (j, t), of indicated mice with inhibitor administration. (a-j) Female 8-week-old NSG mice that were IP injected 50 mg/Kg/day Pavinetant (P50) for 6 days after growth of SC implanted HCC PDX-n for 40 days (n = 6). (k-t) Female 8-week-old NSG mice that were IP implanted 10 mg/Kg/day Fezolinetant (F10) or 50 mg/Kg/day Pavinetant (P50) for 6 days after growth of SC injected HCC-PDX-r progression for 43 days (n = 6). A representative result of two independent experiment is presented as mean ± SEM. Each dot represents one biological replicate. Statistical analysis was conducted by two-tailed unpaired t-test and one-way ANOVA with Bonferroni’s multiple-comparisons test (d-g, i, j, n-q, s, t).

Source Data

Supplementary information

Reporting Summary

Supplementary Table 1

Whole-body TAG and trehalose levels of flies bearing yki3SA tumours with RNAi against different ligands at 29 °C for 8 days.

Supplementary Table 2

The FPKM values of genes expressed in the midguts of flies bearing indicated tumours at 29 °C for 8 days.

Supplementary Table 3

The FPKM values of gene expressed in the Malpighian tubules of indicated tumour-bearing flies at 29 °C for 8 days.

Supplementary Table 4

The FPKM values of target genes of canonical pathways in the Malpighian tubules of tumour-bearing flies at 29 °C for 8 days.

Supplementary Tables 5–8

Supplementary Tables 5–8.

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Xu, W., Li, G., Chen, Y. et al. A novel antidiuretic hormone governs tumour-induced renal dysfunction. Nature 624, 425–432 (2023). https://doi.org/10.1038/s41586-023-06833-8

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