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A Novel Approach To Renal Cell Regeneration

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Scientists at the University of Texas at Dallas have identified a hitherto unidentified “housekeeping” mechanism in kidney cells that eliminates undesirable material, enabling the cells to self-renew and stay functional and healthy.

The self-renewal process helps explain why, in the absence of trauma or illness, kidney health can last a lifetime. This process differs fundamentally from the way other body tissues are believed to regenerate. In a report that was published in Nature Nanotechnology on April 17, the researchers explained the mechanism.

In contrast to the skin and liver, where cells divide to produce new daughter cells and repair the organ, the kidney’s proximal tubule cells are quiescent during mitosis; they do not proliferate. According to Dr. Jie Zheng, co-corresponding author of the study and professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics, kidney cells can repair themselves in mild cases of injury or disease, but only to a limited extent.

Unexpected Discovery

The researchers said that they were unprepared for their discovery.

Zheng has spent the last fifteen years researching the potential applications of gold nanoparticles in medicine, including tailored administration of cancer medications, imaging agents, and a better knowledge of glomerular filtration and early liver disease diagnosis. Understanding how kidneys filter gold nanoparticles and excrete them from the body through urine has been a component of that study.

According to research, gold nanoparticles often enter the proximal tubules, which comprise more than 50% of the kidney, after passing through the glomerulus, a structure in the kidney. It has been demonstrated that the nanoparticles are internalized by proximal tubular epithelial cells and then escape to be expelled in urine. It’s unclear, though, just how they manage to get out of the prisons.

Zheng and his chemistry team, which included research scientist and lead study author Yingyu Huang PhD’20 and co-corresponding author Dr. Mengxiao Yu, research associate professor, were using an optical microscope in December 2021 to examine gold nanoparticles in proximal tubular tissue samples. However, in order to obtain better resolution, they switched to one of the University’s electron microscopes (EM).

“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,” Yu explained.

Vesicles are tiny, fluid-filled sacs that are present both within and outside of cells and are used to carry different materials.

“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,” Yu explained.

In addition to gold nanoparticles, the researchers discovered proximal tubular cells with outwardly facing bulges in their luminal membranes that housed various organelles normally seen solely inside cells, such as lysosomes, mitochondria, and endoplasmic reticulum. Next, a vesicle containing the extruded contents was pinched off and floated into the extracellular space.

“At that moment, we knew this was an unusual phenomenon,” Yu stated. “This is a new method for cells to remove cellular contents.”

A Fresh Approach To Rejuvenation

The mechanism of extrusion-mediated self-renewal is essentially distinct from other recognized regeneration processes, including cell division, and housekeeping activities, like exocytosis. Exocytosis is the process by which foreign materials, such nanoparticles, are enclosed in a vesicle inside the cell. The cell’s membrane then splits openly to let the contents escape, fusing the vesicle membrane with its inside.

“What we found is entirely distinct from what was previously known about how cells get rid of particles. The extrusion method removes outdated content from normal cells and enables them to update themselves with new content because it does not involve membrane fusion, according to Huang. Whether or whether there are foreign nanoparticles present, it still occurs. These cells use an innate, proactive mechanism to extend their lifespan and ensure optimal functionality.”

According to Zheng, their research opens up new fields of inquiry. For instance, artery walls, the stomach, and the digestive system all include epithelial cells, similar to those in the proximal tubules.

In the subject of nanomedicine, our goal is to reduce the amount of nanoparticles that build up within the body as much as we can. “Knowing how nanoparticles are removed from the proximal tubules is crucial because we don’t want them to become lodged in the kidneys,” Zheng stated. Furthermore, if we could figure out how to control or monitor this process of self-renewal, we might be able to prevent kidney disease in those with diabetes or high blood pressure.

“If we could develop ways to detect the signature of this process noninvasively, perhaps it could be an indicator of early kidney disease.”

The National Science Foundation, the Cancer Prevention and Research Institute of Texas, the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124881, R01DK115986, R01DK126140, and R01DK103363), and other funding sources provided funding for the study.