Alvespimycin is identified as a novel therapeutic agent for diabetic kidney disease by chemical screening targeting extracellular vesicles
Extracellular vesicles, often referred to as EVs, are crucial components in how cells communicate with one another. They are also known to significantly influence the regulation of both normal physiological processes and various disease states. In the context of diabetic kidney disease, or DKD, research has indicated that macrophages, which are immune cells that accumulate in the mesangial region of the kidney, may contribute to the disease’s progression by triggering localized inflammation within the glomeruli, the kidney’s filtering units.
A recent area of investigation has centered on the communication mediated by these extracellular vesicles between mesangial cells (MC), a type of cell found in the glomerulus, and macrophages. This EV-mediated interaction is being explored as a potential novel therapeutic target for DKD. Studies have shown that EVs released from mesangial cells can induce an inflammatory response in macrophages, and this inflammatory effect is further amplified when exposed to high-glucose conditions, a characteristic feature of diabetes.
To identify new therapeutic agents capable of inhibiting these EV-mediated mechanisms, researchers turned to drug repositioning, a strategy considered effective for finding new uses for existing drugs. A unique screening strategy was developed to identify agents that would specifically and potently inhibit EV mechanisms while also demonstrating minimal toxicity. Through this screening process, alvespimycin, a known inhibitor of heat shock protein 90 (HSP90), was successfully identified.
When diabetic rats were treated with alvespimycin, significant improvements were observed. The treatment notably suppressed mesangial expansion, a hallmark of DKD, and reduced the activation of inflammatory genes, including those indicative of macrophage activity. Furthermore, proteinuria, the presence of excess protein in the urine and a key indicator of kidney damage, was also significantly decreased. It is particularly noteworthy that the inhibitory effect of alvespimycin on EV uptake was found to be specific to this compound when compared to other known HSP90 inhibitors.
These findings suggest that extracellular vesicles derived from mesangial cells play a critical role in promoting inflammation through the intercellular communication between mesangial cells and macrophages in diabetic kidney disease. The fact that alvespimycin effectively ameliorated the progression of DKD by suppressing these EV-mediated actions highlights a promising new direction. This research strongly suggests that therapeutic agents specifically targeting extracellular vesicle mechanisms could represent a novel and effective strategy for treating diabetic kidney disease.