Video Experimental Relacionado

Updated: Jan 28, 2026

Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis

Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis

Published on: April 25, 2025

Potencial Terapéutico del Inhibidor de HSP90 17-DMAG en la Regulación de METTL3 para el Tratamiento de la Fibrosis

Soo Min Lee¹, Myoung Seok Lee², Hae Rim Jung³

¹College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.

Journal of the American Society of Nephrology : JASN

|January 26, 2026

Abstracto

Background:

Kidney fibrosis is a major pathological feature of chronic kidney disease (CKD), characterized by excessive deposition of extracellular matrix proteins, leading to progressive loss of kidney function. N6-methyladenosine (m6A) RNA methylation has emerged as a crucial epigenetic modification implicated in various diseases, including kidney fibrosis. METTL3, an m6A "writer," plays a key role in promoting fibrosis by stabilizing profibrotic gene expression. Therefore, targeting METTL3 represents a promising therapeutic strategy for CKD treatment. In this study, we explored the therapeutic potential of 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in regulating METTL3 to mitigate kidney fibrosis.

Methods:

Through transcriptome-based drug repositioning, we identified 17-DMAG as a potential inhibitor of METTL3. Differentially expressed gene (DEG) analysis was performed to assess the enrichment of 17-DMAG in CKD-related gene expression profiles. The antifibrotic effects of 17-DMAG were evaluated in vitro and in vivo models. Mechanism of 17-DMAG in downregulating METTL3 was also investigated.

Results:

17-DMAG significantly reduced METTL3 expression in renal epithelial cells in a dose- and time-dependent manner. In vivo mouse models of kidney fibrosis, 17-DMAG treatment attenuated METTL3 levels, reduced total m6A modification, and effectively mitigated fibrosis, as evidenced by decreased collagen deposition and profibrotic marker expression. Mechanistically, 17-DMAG, a heat shock protein 90 (HSP90) N-terminal inhibitor, induced a heat shock response that sequentially upregulated HSP70 expression. The elevated HSP70 levels inhibited c-Jun N-terminal kinase (JNK) activity, thereby suppressing the c-Jun transcription factor and ultimately leading to the downregulation of METTL3 expression. MeRIP-Seq analysis revealed that 17-DMAG reversed unilateral ischemia-reperfusion injury-induced m6A epitranscriptomic changes in fibrosis-related genes, including Gsk3b, which is involved in fibrotic pathways.

Conclusions:

N-terminal HSP90 inhibition, along with subsequent c-Jun suppression, contributed to the mechanism underlying 17-DMAG-induced METTL3 downregulation. Through this regulatory pathway, 17-DMAG effectively suppressed METTL3 expression and attenuated kidney fibrosis in both in vitro and in vivo models.

Palabras clave:

fibrosis renal METTL3 17-DMAG enfermedad renal crónica HSP90 c-Jun epigenética modificación de ARN reposición de fármacos

Más Videos Relacionados

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma

Published on: May 24, 2024

Evaluating Therapeutic Interventions in the SHIP-deficient Mouse Model of Crohn Disease-like Ileitis and Fibrosis

Evaluating Therapeutic Interventions in the SHIP-deficient Mouse Model of Crohn Disease-like Ileitis and Fibrosis

Published on: October 14, 2025

Videos de Conceptos Relacionados

Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors

Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors

Phosphodiesterase 5 (PDE5) inhibitors are potent enzymes that function to hydrolyze cyclic nucleotides to their corresponding 5' monophosphates. Their unique biochemical properties have been applied in treating Pulmonary Arterial Hypertension (PAH).
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...

Eukaryotic Transcription Inhibitors

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...

Kidney Structure

Kidney Structure

The kidneys are two large bean-shaped organs located in the upper abdomen. They filter the blood several times a day to remove toxins and rebalance water and electrolytes of the circulatory system via the renal veins. The kidneys receive blood directly from the heart via the renal arteries. These arteries enter the kidney at the hilum, the concave surface of the bean, where they branch and divide into smaller vessels and capillaries.

Hormonal Regulation

Hormonal Regulation

The renin-aldosterone system is an endocrine system which guides the renal absorption of water and electrolytes, thus managing blood pressure and osmoregulation. Activation of the system begins in the kidneys with a small cluster of cells adjacent to the afferent and efferent blood vessels of the renal corpuscle. As the nephrons are filtering blood, juxtaglomerular cells monitor blood pressure. If they detect a decrease in pressure, they release the hormone renin into the bloodstream.

Negative Regulator Molecules

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.

Cystic Fibrosis: Pathogenesis

Cystic Fibrosis: Pathogenesis

Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...