On December 7th 2023, Beijing time, a research paper titled "A novel antidiuretic hormone governs tumour-induced renal dysfunction" by a team led by Professor Wei Song and Associate Professor Xujun Ye from Wuhan University was published online in Nature. The research delves into the interaction between tumors and kidneys.

The paper's co-first authors are graduate student Wenhao Xu and postdoctoral researcher Li Gerui, with graduate student Chen Yuan contributing as a co-author. Wuhan University is the sole affiliated institution for this research.

Maintaining Kidney Function Crucial for Health

Proper kidney function and fluid balance are essential for all animals, including vertebrates and invertebrates, to handle various physiological and pathological stresses. Patients with malignant tumors often experience renal dysfunction and oliguria (reduced urine output), hindering fluid excretion and toxin removal, posing a significant threat to their health. Dialysis is currently the only treatment option for tumor-induced renal dysfunction due to the unknown pathogenesis.

Prior studies have primarily focused on the kidney toxicity of anti-tumor drugs. However, nearly half of patients with solid tumors develop renal dysfunction even before treatment initiation. This suggests potential causative factors beyond drug toxicity, such as tumor-related immune or inflammatory responses. However, whether malignant tumors directly target and disrupt the normal function of kidneys still remains unaddressed.

New Antidiuretic Hormone Identified in Fruit Flies

Water transport across renal tubular epithelial cells is a vital step in body fluid drainage, a process regulated by hormones and shared across various species, including humans and fruit flies. While diuretic hormones that promote urine output exist in both humans and Drosophila (fruit flies), researches on their counterparts antidiuretic hormones have been limited. No clear antidiuretic hormone has been identified in Drosophila, and the sole human antidiuretic hormone, arginine vasopressin (AVP), fails to explain many physiological and pathological control mechanisms.

To address these gaps, Professor Wei Song and Associate Professor Xujun Ye's team utilized established Drosophila tumor models and high-throughput in vivo screening to identify the first-ever antidiuretic hormone in fruit flies: the isoform F ion transport peptide (ITP-F). They discovered that ITP-F is secreted by malignant tumors and enteroendocrine cells. It directly acts on the Drosophila Malpighian tubules (analogous to human renal tubules), disrupting the excretion function and causing severe fluid retention.

Mechanism and Potential Therapeutic Target

The specific molecular mechanism involves ITP-F directly activating the G protein-coupled receptor TkR99D and its downstream NOS-cGMP signaling pathway in Malpighian epithelial stellate cells, ultimately inhibiting fluid discharge.

Furthermore, the research team discovered that the mammalian neurokinin 3 receptor (NK3R), a homolog of Drosophila TkR99D, is present in renal tubular epithelial cells. Blocking NK3R with small molecule drugs effectively improved renal tubular dysfunction in mice with various malignant tumors.

This groundbreaking work sheds light on a novel antidiuretic pathway mediating cross-species tumor-kidney interaction. It holds promise for the development of new therapeutic targets for cancer-related renal dysfunction.

Full text link: https://www.nature.com/articles/s41586-023-06833-8