Mapping the interplay between PVT-1, a non-coding RNA targeting common mechanisms of acute and chronic kidney diseases, and the Hippo pathway
Background
Acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), and renal cell carcinoma (RCC) are diverse kidney diseases with an increasing global prevalence. Despite clinical differences, these diseases share common pathological pathways: tubular epithelial cell injury, chronic inflammation, and fibrotic remodeling. Current treatments only alleviate symptoms, lacking common molecular targets for fundamental kidney protection and simultaneous control of various kidney diseases. The Hippo signaling pathway, which maintains tissue homeostasis and regulates epithelial-to-mesenchymal transition, has emerged as a potential therapeutic target. Furthermore, plasmacytoma variant translocation-1 (PVT-1), a long non-coding RNA (lncRNA) regulating gene expression, has been identified as a key regulator of kidney injury responses, sparking interest in developing integrated therapies.
Key Findings
The researchers discovered that PVT-1, which abnormally increases in kidney injury, interacts closely with key factors in the Hippo signaling pathway. In normal kidney tissue, the Hippo pathway is active, suppressing cell proliferation and maintaining homeostasis. However, when epithelial cells are damaged, this signal is inhibited, causing YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) transcriptional regulators to translocate to the nucleus, leading to fibrosis and abnormal proliferation. The molecular mechanism revealed in this analysis shows that cytoplasmic PVT-1 acts as a sponge, sequestering microRNAs such as miR-186, or blocking upstream inhibitors of the Hippo pathway, thereby abnormally activating YAP/TAZ. Consequently, oxidative stress is induced in tubular cells, and excessive extracellular matrix accumulates, accelerating kidney fibrosis. Notably, the researchers proposed a specific therapeutic strategy by controlling the link between PVT-1 and the Hippo pathway using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing technology. The results showed that specifically inhibiting PVT-1 transcription with gene scissors significantly blocked epithelial-to-mesenchymal transition in tubular epithelial cells and reduced the secretion of inflammatory cytokines. In a renal cell carcinoma model, PVT-1 inhibition also inhibited uncontrolled proliferation of cancer cells and induced apoptosis. This opens the way to control the pathological symptoms of multiple kidney diseases by regulating a single target gene.
Significance and Outlook
This research lays the foundation for multifunctional gene targets that can treat both acute and chronic kidney diseases. The interaction between PVT-1 and the Hippo signaling pathway is expected to become a key pathway for developing new drugs to prevent kidney fibrosis. Furthermore, measuring the concentration of PVT-1 in body fluids may enable the development of non-invasive biomarkers for diagnosing the extent of kidney damage or the prognosis of renal cell carcinoma. However, to apply this to actual patient treatment, it is necessary to overcome the limitations of in vivo delivery technology. It is essential to develop a highly sophisticated drug delivery system that specifically targets gene scissors or non-coding RNA-targeted therapeutic agents to renal tubular cells. In addition, since the Hippo signaling pathway is involved in the cellular physiology of other tissues, subsequent validation studies are required to minimize potential side effects and ensure kidney tissue specificity during systemic administration.
Why It Matters
This discovery can be translated into gene therapies that delay kidney dialysis or help preserve kidney function in patients awaiting kidney transplantation. In clinical settings, injecting a CRISPR-dCas9 system into patients with chronic kidney disease to lower PVT-1 expression may delay the progression of tubular fibrosis. In the field of cancer, targeting and inhibiting PVT-1 in the tumor tissue of patients with renal cell carcinoma may control the proliferation of cancer cells that are resistant to existing anticancer drugs and maximize the therapeutic response in combination therapy. Furthermore, periodically monitoring PVT-1 levels in urine or blood may accelerate the development of precision medicine solutions, such as diagnostic kits for early diagnosis of early signs of worsening chronic kidney disease.
Globally, the number of patients suffering from a diverse spectrum of kidney diseases, including parenchymal acute kidney injury (AKI), chronic kidney diseases (CKD), which includes diabetic kidney disease (DKD), and other chronic nephropathies, along with malignant renal cell carcinoma (RCC), is rising rapidly. Although they exhibit clinical heterogeneity, these conditions share common pathomechanisms, including tubular epithelial injury, inflammation, and progressive fibrosis, yet lack unified pharmacological targets that can address this spectrum simultaneously. Among these pathways, the Hippo signaling pathway has emerged as a key regulator of renal tissue homeostasis, epithelial plasticity, and fibrotic remodeling. Additionally, long non-coding RNAs (lncRNAs) are emerging coordinators of renal injury responses, with plasmacytoma variant translocation-1 (PVT-1) gaining significant attention as a pleiotropic renal disease transcript. Growing evidence indicates that lncRNA PVT-1 is dysregulated in conditions of intrinsic parenchymal kidney diseases as well as malignant tumors, and that it contributes to inflammatory signaling, tubular injury, extracellular matrix deposition, oxidative stress, and abnormal cellular proliferation. Thus, lncRNA PVT-1 may serve as a context-dependent therapeutic target across a variety of diseases. However, the precise regulatory role of lncRNA PVT-1 in Hippo signaling in the context of kidney diseases remains poorly understood. Hence, this review summarizes the role of lncRNA PVT-1 in renal physiology and various pathologies, discusses the growing role of Hippo signaling in kidney homeostasis, proposes a mechanistic framework linking lncRNA PVT-1 to Hippo-mediated kidney injury, addresses emerging pharmacological strategies, including CRISPR technologies targeting this axis, and explores its biomarker potential to diagnose and mitigate various kidney diseases.
This discovery can be translated into gene therapies that delay kidney dialysis or help preserve kidney function in patients awaiting kidney transplantation. In clinical settings, injecting a CRISPR-dCas9 system into patients with chronic kidney disease to lower PVT-1 expression may delay the progression of tubular fibrosis. In the field of cancer, targeting and inhibiting PVT-1 in the tumor tissue of patients with renal cell carcinoma may control the proliferation of cancer cells that are resistant to existing anticancer drugs and maximize the therapeutic response in combination therapy. Furthermore, periodically monitoring PVT-1 levels in urine or blood may accelerate the development of precision medicine solutions, such as diagnostic kits for early diagnosis of early signs of worsening chronic kidney disease.