New findings might help…
In the liver and skin, cells divide to make new daughter cells and rebuild the organ. In the proximal tubules of the kidney, however, cells are mitotically inactive, which means that they do not divide to make new cells. Kidney cells do have a limited capacity for repair in cases of minor illness or injury, and kidney stem cells can generate new kidney cells, but only to a certain extent.
When kidney cells are badly damaged, they often die and cannot recover. Your kidney will simply stop working eventually. That presents a significant problem in the treatment of renal disease.
Right now, all we can do is delay the development of renal failure. If the organ is significantly damaged or afflicted with a long-term illness, we cannot readily heal it.
Researchers from the University of Texas at Dallas have uncovered a previously unknown process in kidney cells, referred to as a “housekeeping” mechanism. This process expels unwanted content from the cells, allowing them to rejuvenate and maintain their functionality and health.
Dr. Jie Zheng, a Distinguished Chair in Natural Sciences and Mathematics, says, “discovering this self-renewal mechanism is probably one of the most significant findings we’ve made so far.”
Unlike the regeneration process observed in other bodily tissues, this self-renewal mechanism provides insight into how the kidneys can remain healthy throughout a person’s lifetime, barring any injury or disease.
The researchers published their findings on this mechanism in a study featured in Nature Nanotechnology.
The discovery came as a surprise to the researchers. Dr. Zheng had been studying the biomedical applications of gold nanoparticles for 15 years, primarily focusing on their use as imaging agents, understanding glomerular filtration, detecting liver disease early on, and delivering cancer drugs to targeted areas. Part of their investigation involved understanding how gold nanoparticles are filtered by the kidneys and expelled through urine.
Previous studies have indicated that gold nanoparticles generally pass through the glomerulus, a structure in the kidney, without damage and then travel into the proximal tubules, which constitute more than 50% of the kidney. It has been observed that proximal tubular epithelial cells internalize these nanoparticles, which are eventually excreted in urine after escaping from the cells. However, the exact mechanism of their escape has remained unclear.
In December 2021, Dr. Zheng and his chemistry team, including research scientist and lead study author Yingyu Huang PhD’20 and co-corresponding author Dr. Mengxiao Yu, a research associate professor, initially examined gold nanoparticles in proximal tubular tissue samples using an optical microscope. However, they switched to an electron microscope (EM) available at the university to achieve better resolution.
“Using the EM, we saw gold nanoparticles encapsulated in lysosomes inside of large vesicles in the lumen, which is the space outside the epithelial cells,” explained Dr. Yu.
Vesicles are small fluid-filled sacs found both inside and outside cells, responsible for transporting various substances.
“But we also observed the formation of these vesicles containing both nanoparticles and organelles outside of cells, and it was not something we had seen before,” Dr. Yu added.
The researchers identified proximal tubular cells that had developed outwardly facing bulges in their luminal membranes. These bulges contained not only gold nanoparticles but also lysosomes, mitochondria, endoplasmic reticulum, and other organelles typically confined to the cell’s interior. The expelled contents were then pinched off into a vesicle, which subsequently floated into the extracellular space.
“At that moment, we knew this was an unusual phenomenon,” Yu remarked. “This is a new method for cells to remove cellular contents.”
The extrusion-mediated self-renewal mechanism discovered in this study stands in stark contrast to other known regenerative processes, such as cell division, as well as typical cellular processes like exocytosis. In exocytosis, foreign substances, including nanoparticles, are enclosed within a vesicle inside the cell. Subsequently, the vesicle membrane fuses with the inner membrane of the cell, leading to the release of its contents outside.
“What we discovered is totally different from the previous understanding of how cells eliminate particles. There is no membrane fusion in the extrusion process, which eliminates old content from normal cells and allows the cells to update themselves with fresh contents,” explained Huang. “It happens whether foreign nanoparticles are present or not. It’s an intrinsic, proactive process these cells use to survive longer and function properly.”
Dr. Zheng emphasized that these findings open up new avenues for research. For instance, epithelial cells, similar to those found in the proximal tubules, are present in other tissues such as the arterial walls, gut, and digestive tract.
“In the field of nanomedicine, we want to minimize accumulation of nanoparticles in the body as much as possible. We don’t want them to get stuck in the kidneys, so it’s very important to understand how nanoparticles are eliminated from the proximal tubules,” said Dr. Zheng said. “Also, if we could learn how to regulate or monitor this self-renewal process, we might find a way to keep kidneys healthy in patients with high blood pressure or diabetes.
Dr. Zheng further suggested that noninvasive detection of the signature of this self-renewal process could potentially serve as an early indicator of kidney disease. Developing methods to detect this process could enable the identification of kidney issues at an early stage, allowing for timely intervention and treatment.