The neuropeptide substance P drives kidney fibrosis through its receptor NK-1R, and blocking this receptor — either genetically or with drugs — significantly reduces kidney inflammation and scarring in mice.
NK-1R knockout = reduced fibrosisMice lacking the NK-1R receptor were significantly protected from kidney inflammation and scarring after ureteral obstruction, confirming the receptor as a direct driver of renal fibrosis
What the researchers found
The neuropeptide substance P (SP) and its receptor NK-1R were found to be elevated in both patients with chronic kidney disease and in mice with induced kidney obstruction. Higher SP/NK-1R levels correlated with worse kidney fibrosis and declining kidney function.
Adding substance P to mice with kidney obstruction worsened inflammation and fibrosis, while genetically knocking out NK-1R or blocking it with a drug significantly reduced these effects. The researchers uncovered the mechanism: a transcription factor called TFAP4 drives NK-1R production, and once substance P activates NK-1R, it triggers the JNK/p38 signaling pathways. This causes kidney tubular cells to stop growing, undergo programmed cell death, and switch on scar-producing genes.
Why it matters
This study bridges neuropeptide biology and kidney disease in a way that has direct therapeutic implications. Substance P is best known for its role in pain signaling, but this research shows it also drives kidney inflammation and scarring through NK-1R. Importantly, NK-1R antagonists already exist as approved drugs for other conditions (such as the anti-nausea drug aprepitant), which means repurposing these medications for chronic kidney disease could be a relatively fast path to clinical testing.
The numbers in context
SP and NK-1R elevated in CKD patients · serum SP correlated with fibrosis severity · NK-1R knockout mice protected from UUO-induced fibrosis · JNK/p38 pathway activation confirmed · TFAP4 identified as NK-1R transcriptional driver
How the study worked
This was a multi-approach study combining human clinical samples with animal and cell models. The researchers analyzed kidney biopsy tissue and serum from patients with and without CKD. They used NK-1R knockout mice, substance P treatment, and a pharmacological NK-1R antagonist in a unilateral ureteral obstruction (UUO) mouse model of kidney fibrosis. Cell-level mechanisms were explored using NK-1R-overexpressing human kidney tubular cells (HK-2). Promoter binding analysis identified TFAP4 as the transcription factor driving NK-1R expression.
Who was studied
Human CKD patients (kidney biopsies and serum), NK-1R knockout mice, UUO mouse model, and HK-2 human kidney cell lines
What this study cannot tell us
The mouse model (UUO) represents obstructive kidney disease, which is only one cause of CKD and may not fully represent other forms like diabetic or hypertensive nephropathy. The human component was observational (biopsy and serum analysis), so it shows correlation but not causation in people. Specific patient numbers and clinical outcomes were not detailed in the abstract.
How to read the evidence
This study earns a moderate evidence grade because it combines human clinical observations (kidney biopsies and serum from CKD patients) with robust mechanistic work in knockout mice and cell cultures. However, no interventional human trial was conducted.
When this study was published
Published in 2023, this is a recent study and its findings are current with the state of neuropeptide and kidney fibrosis research.
The bigger picture
This study reveals an unexpected connection between the nervous system's pain-signaling peptide (substance P) and the progression of kidney disease. It adds NK-1R to the growing list of druggable targets for renal fibrosis and is especially exciting because NK-1R antagonists like aprepitant are already FDA-approved for other uses. The concept of neuropeptide-driven organ fibrosis may extend beyond the kidneys — similar mechanisms could be at play in liver, lung, and cardiac fibrosis.
Questions still open
- Could existing NK-1R antagonists like aprepitant be repurposed in clinical trials for chronic kidney disease?
- Does substance P/NK-1R signaling contribute to fibrosis in other organs such as the liver or lungs?
- What role does TFAP4-driven NK-1R upregulation play in other inflammatory kidney conditions beyond obstructive nephropathy?
Common questions
What is substance P and why does it matter for kidney disease?
Are there already drugs that block NK-1R?
Read the original research
Targeting NK-1R attenuates renal fibrosis via modulating inflammatory responses and cell fate in chronic kidney disease.
Frontiers in immunology, 14, 1142240
Citation
Zhu, Enyi; Liu, Yang; Zhong, Ming; Liu, Yu; Jiang, Xi; Shu, Xiaorong; Li, Na; Guan, Hui; Xia, Yin; Li, Jinhong; Lan, Hui-Yao; Zheng, Zhihua. (2023). Targeting NK-1R attenuates renal fibrosis via modulating inflammatory responses and cell fate in chronic kidney disease.. Frontiers in immunology, 14, 1142240. https://doi.org/10.3389/fimmu.2023.1142240