Maintaining renal function and fluid balance is essential for vertebrates and invertebrates to cope with various physiological and pathological stresses. Patients with malignant tumors often have renal dysfunction and oliguria, which leads to impaired fluid excretion and toxin clearance, which seriously endangers the health of the body. Due to the unknown pathogenesis, dialysis is the only option for tumor-related renal dysfunction. Previous studies in this field have focused on the nephrotoxicity of antineoplastic drugs, but nearly half of patients with solid tumors develop renal dysfunction at the time of diagnosis and before **Tumor-related immune or inflammatory responses are also considered to be potential genogens. However,Whether and how malignant tumors directly target the kidneys and disrupt their physiological functions is still largely unknown. The transport of water molecules by renal tubular epithelial cells is a critical step in the body's drainage and is present in different species, including humans and fruit flies, and is hormonally regulated. There are a variety of diuretics that promote tubular drainage in both humans and Drosophila, but research on their opposing antidiuretic effects is very limited. There is currently no definite antidiuretic in Drosophila, the only antidiuretic in the human bodyArginine vasopressin**p) is also difficult to explain many physiological and pathological regulations. On December 6, 2023, the Medical Research Institute of Wuhan University, the Frontier Science Center of Immunology and Metabolism of the Ministry of Education, the Medical Research Institute of Zhongnan Hospital, and the Taikang Life Medicine CenterSong WeiThe team worked with the Department of Geriatrics, Zhongnan Hospital, Wuhan UniversityYe XujunThe team is innaturepublished ona novel antidiuretic hormone governs tumour-induced renal dysfunctionThe article, through conserved Drosophila tumor models and high-throughput in vivo screening, was unexpectedThe first definite case of antidiuretic-ITPF in Drosophila was identified, and it was revealed that it was secreted by malignant tumors and intestinal endocrine cells, directly acting on Drosophila Malcolt ducts (similar to human renal tubules), disrupting its drainage function and leading to severe fluid retention。Molecular mechanisms include ITPF activating the GPCR receptor TKR99D and its downstream NOS-cGMP signaling pathway in martensian stellate epithelial cells, inhibiting fluid excretion. Plus, they also found:Mammalian neurokinin 3 receptor (NK3R) is expressed as a homolog of Drosophila TKR99D in renal tubular epithelial cells, and blocking NK3R by small molecule drugs can effectively improve renal tubular dysfunction caused by multiple malignant tumors in mice. 
The research team first hypothesized that tumors produce secreted proteins directed at the kidneys, which impair kidney function and lead to fluid retention, independent of other host depletion effects such as lipid loss and muscle wasting. RNA screening of 112 upregulated secreted proteins in Drosophila YKI3SA tumors revealed that ITP (Ion Trasnport Peptide) was essential for tumor-induced fluid retention and hyperglycemia, but not for lipid loss or muscle dysfunction. At the same time, they also broad-spectrum found that Drosophila NDN, RASV12 intestinal tumors, and LGL--, RASV12 eyecup tumors can also lead to fluid retention by secreting ITP. There are five different RNA subtypes of Drosophila ITP, and the research team developed RNAi and overexpression lines for each subtype, and finally the study proved that the ITPF produced by the tumor is a key functional subtype, which directly leads to fluid retention. It is worth noting that ectopic expression of ITPF in muscle or adipose tissue of normal Drosophila without tumors can also significantly lead to fluid retention, including direct inhibition of water transport in Drosophila malcolt (renal tubules). As a result, the research team defined ITPF as the first unambiguous case of antidiuretic in Drosophila. To study the molecular mechanism, the research team explored different types of Drosophila Malcolski cells and different downstream pathways, including the transformation of the mammalian reporter gene FLINCG2 into Drosophila to study CGMP changes, and finally found that ITPF directly activates the CGMP signaling pathway in Malcolski stellar epithelial cells. The LEXA-GAL4 dual expression system is a necessary tool to study organ communication in Drosophila in vivo, and the research team spent nearly 2 years to construct the LEXA system for ectopic ITPF expression and YKI3SA intestinal tumors, and combined with the traditional GAL4 system, the NOS-cGMP signaling pathway in in vivo in mahmale stellar-shaped epithelial cells (rather than master cells) is essential for the antidiuretic function of ITPF. In order to explore the functional receptors that respond to ITPF, the research team focused on GPCR based on the downstream cGMP pathway, and finally determined that TKR99D is the receptor for ITPF through single-cell RNA seq, biochemical experiments, and in vivo dual-expression system RNAi validation, in addition to elucidating the competitive activation of TKR99D between ITPF and the classical ligand TK. Although no mammalian ITPF homolog has been identified, the research team found that mouse and human NK3R are homologs of the Drosophila receptor TKR99D, and noted that it is mainly expressed in proximal renal tubular epithelial cells. By testing different mouse models of malignant tumors, the research team found that tumor-bearing mice in at least the Apcmin+ intestinal tumor model, the LLC lung cancer model, the MFC gastric cancer model, the HCT116 gastric cancer model, and the PDX gastric cancer model all showed varying degrees of kidney injury and urination disorders, and intraperitoneal injection of small molecule inhibitors to block NK3R activity was effective in alleviating the kidney injury and voiding disorders induced by malignant tumors. 
In summary, the research team identified ITPF as the first case of antidiuretic in Drosophila, which mediates tumor-induced kidney injury and drainage disorders by activating the receptor TKR99D, while multiple malignancies in mice also cause similar tubular damage and drainage disorders through NK3R (TKR99D homolog). Relative to the current interpretation of tumor-related renal dysfunction, such as anti-tumor drug nephrotoxicity and systemic inflammatory responseThe study provides new insights and targets for tumor-kidney interactions and cancer-related renal dysfunction. 
Pseudo-Van Gogh technique symbolizes antidiuretic blocking drainage (AI mapping) Xu Wenhao, a doctoral student at Wuhan University, and Li Gerui, a postdoctoral fellow, are the co-first authors, doctoral student Chen Yuan is the co-author, and Professor Song Wei and Associate Professor Ye Xujun are the co-corresponding authors. Original link:Recruitment information: Song Wei's team has long focused on organ communication and metabolic immune regulation, combined with Drosophila, mice and clinical observation to study the remote regulation of secreted proteins mediated by intestinal or malignant tumors on tissues such as kidney (nature, immunity), pancreas (cell discovery, cell rep), fat and muscle (cell metab, dev cell), etc., revealing new pathogenesis and** Target, long-term recruitment of postdoctoral researchers in cell biology, developmental biology, molecular biology, basic medicine and other directions, interested parties contact: [email protected] Ye Xujun's team focuses on the basic and clinical research of aging-related chronic diseases, including pulmonary fibrosis, kidney injury and cardiometabolic diseases, and has presided over 7 national scientific research and teaching projects, and the research results have won the second prize of Hubei Provincial Science and Technology Progress Award and the third prize of Science and Technology Promotion. Long-term recruitment of postdoctoral researchers interested in geriatrics, molecular mechanism research of organ aging and chronic age-related diseases, real-world big data research related to healthy aging, etc., interested parties contact: [email protected]
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