University of Texas at Dallas scientists have discovered a previously unknown “housekeeping” process in kidney cells that ejects unwanted content, leading to cells that rejuvenate themselves and remain functioning and healthy.

The self-renewal process, which is fundamentally different from how other bodily tissues are thought to regenerate, helps explain how, barring injury or disease, the kidneys can remain healthy for a lifetime. The researchers described the mechanism in a study published April 17 in Nature Nanotechnology.

Unlike the liver and skin, where cells divide to create recent daughter cells and regenerate the organ, cells within the proximal tubules of the kidney are mitotically quiescent -; they don’t divide to create recent cells. In cases of mild injury or disease, kidney cells do have limited repair capabilities, and stem cells within the kidney can form recent kidney cells, but only up to a degree, said Dr. Jie Zheng, professor of chemistry and biochemistry within the School of Natural Sciences and Mathematics and co-corresponding creator of the study.

In most scenarios, if kidney cells are severely injured, they are going to die, and they can’t regenerate. Your kidney will just fail in the end. That is a giant challenge in health management for kidney disease. All we are able to do currently is decelerate the progression to kidney failure. We cannot easily repair the organ if it’s injured severely or by chronic disease.

That is why discovering this self-renewal mechanism might be one of the significant findings we have made to date. With excellent core facilities and dedicated staff, UTD is a fantastic place to do such cutting-edge research.”

Dr. Jie Zheng, a Distinguished Chair in Natural Sciences and Mathematics

Further research may result in improvements in nanomedicine and early detection of kidney disease, he said.

An unexpected finding

The researchers said their discovery took them by surprise.

For 15 years, Zheng has been investigating the biomedical use of gold nanoparticles as imaging agents, for fundamental understanding of glomerular filtration, for early detection of liver disease, and for targeted delivery of cancer drugs. A part of that work has focused on understanding how gold nanoparticles are filtered by the kidneys and cleared from the body through urine.

Research has shown that gold nanoparticles generally pass unscathed through a structure within the kidney called the glomerulus after which travel into proximal tubules, which make up over 50% of the kidney. Proximal tubular epithelial cells have been shown to internalize the nanoparticles, which eventually escape those cells to be excreted in urine. But just how they escape the cells has been unclear.

In December 2021, Zheng and his chemistry team -; research scientist and lead study creator Yingyu Huang PhD’20 and co-corresponding creator Dr. Mengxiao Yu, research associate professor -; were examining gold nanoparticles in proximal tubular tissue samples using an optical microscope, but they switched to certainly one of the University’s electron microscopes (EM) for higher resolution.

“Using the EM, we saw gold nanoparticles encapsulated in lysosomes inside of huge vesicles within the lumen, which is the space outside the epithelial cells,” Yu said.

Vesicles are small fluid-filled sacks found each inside and out of doors of cells that transport various substances.

“But we also observed the formation of those vesicles containing each nanoparticles and organelles outside of cells, and it was not something we had seen before,” Yu said.

The researchers found proximal tubular cells that had formed outwardly facing bulges of their luminal membranes that contained not only gold nanoparticles but in addition lysosomes, mitochondria, endoplasmic reticulum and other organelles typically confined to a cell’s interior. The extruded contents were then pinched off right into a vesicle that floated off into the extracellular space.

“At that moment, we knew this was an unusual phenomenon,” Yu said. “This can be a recent method for cells to remove cellular contents.”

A recent renewal process

The extrusion-mediated self-renewal mechanism is fundamentally different from other known regenerative processes -; reminiscent of cell division -; and housecleaning tasks like exocytosis. In exocytosis, foreign substances reminiscent of nanoparticles are encapsulated in a vesicle contained in the cell. Then, the vesicle membrane fuses with the inside the cell’s membrane, which opens to release the contents to the skin.

“What we discovered is completely different from the previous understanding of how cells eliminate particles. There isn’t any membrane fusion within the extrusion process, which eliminates old content from normal cells and allows the cells to update themselves with fresh contents,” Huang said. “It happens whether foreign nanoparticles are present or not. It’s an intrinsic, proactive process these cells use to survive longer and performance properly.”

Zheng said their findings open up recent areas of study. For instance, epithelial cells, like those within the proximal tubules, are present in other tissues, reminiscent of the partitions of arteries and within the gut and digestive tract.

“In the sphere of nanomedicine, we would like to reduce accumulation of nanoparticles within the body as much as possible. We don’t desire them to get stuck within the kidneys, so it is very essential to grasp how nanoparticles are eliminated from the proximal tubules,” Zheng said. “Also, if we could learn learn how to regulate or monitor this self-renewal process, we would discover a technique to keep kidneys healthy in patients with hypertension or diabetes.

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

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124881, R01DK115986, R01DK126140 and R01DK103363), the National Science Foundation and the Cancer Prevention and Research Institute of Texas.

Source:

University of Texas at Dallas

Journal reference:

Huang, Y., et al. (2023). Proximal tubules eliminate endocytosed gold nanoparticles through an organelle-extrusion-mediated self-renewal mechanism. Nature Nanotechnology. doi.org/10.1038/s41565-023-01366-7.