Research reveals how aging cells can be an underlying cause of kidney damage

WASHINGTON – A study in mice by researchers at Georgetown Lombardi Comprehensive Cancer Center has found that stress and tissue damage initiated by angiotensin II, a molecule that is known to increase blood pressure and stiffening in the linings of blood vessels, leads to cellular senescence, a process by which a cell ages and permanently stops dividing but does not die. Importantly, when the researchers eliminated senescent cells from the mice, tissues returned to a normal state in spite of a continued infusion of angiotensin II.

The findings appear in Frontiers in Cell and Developmental Biology on December 8, 2021.

“We’ve known that angiotensin II can lead to hypertension and cellular damage, but our findings show that chronic, stress-induced damage due to slightly elevated blood pressure could be reduced by eliminating senescent cells,” says Irfan Khan, an MD/PhD candidate in the Tumor Biology program at Georgetown University and first author. “By preventing the harmful effects of angiotensin II, we revealed a novel mechanism for eliminating senescent cells that could potentially be used to develop targeted drugs to eliminate these cells.”

The researchers chose angiotensin II as the tool to best induce chronic stress because they could regulate its administration and induce a measured stress level similar to that seen in people who see a slow rise in blood pressure over a lifetime. This stress typically results in less flexibility in the lining of blood vessels, which in turn leads to higher blood pressure. The researchers discovered that these effects are particularly pronounced in the kidneys and not in the brain or lungs, which is what they expected when they started their experiments.

“We can give people angiotensin lowering drugs to treat their high blood pressure. But they have to be given continuously for a lifetime and may need to be combined with other drugs to improve their efficacy. There is a pressing need to address the serious systemic effects of high blood pressure and come up with novel treatments to avoid or reverse damage to the kidneys,” says Anton Wellstein, MD, PhD, professor of oncology and pharmacology at Georgetown Lombardi and corresponding author for this article. “Essentially, we’re building the biological basis for a new therapeutic approach to address the senescence aspect of disease that has mostly been unexplored and untreated. Eliminating senescent cells with a tolerable, short-term therapy could potentially alleviate chronic cardiovascular disease and reduce the need for a lifetime of therapy.”

The researchers don’t think anti-senescence drugs are going to be the fountain of youth, but they hope to be able to reverse some premature tissue damage. “A senescence drug would probably be a very short-term treatment, maybe just a few days to two weeks,” Wellstein says. “Rather than constantly trying to dampen down high blood pressure, we propose getting rid of the senescent cells so that a physician could more easily treat the primary causes.”

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In addition to Khan and Wellstein, the other authors from Georgetown include Marcel O. Schmidt, Bhaskar Kallakury, Sidharth Jain, Shaunt Mehdikhani, Moshe Levi, Margarida Mendenoca, William Welch, Anna T. Riegel and Christopher S. Wilcox.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The research was supported by NIH grants P01 HL-68686 and F30 CA243357-01 as well as grants from the Hypertension Foundation and Georgetown University Institutional Funds.

About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute (NCI) as a comprehensive cancer center. A part of Georgetown University Medical Center, Georgetown Lombardi is the only comprehensive cancer center in the Washington D.C. area. It serves as the research engine for MedStar Health, Georgetown University’s clinical partner. Georgetown Lombardi is also an NCI recognized consortium with John Theurer Cancer Center/Hackensack Meridian Health in Bergen County, New Jersey. The consortium reflects an integrated cancer research enterprise with scientists and physician-researchers from both locations. Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic, translational and clinical research, patient care, community education and outreach to service communities throughout the Washington region, while its consortium member John Theurer Cancer Center/Hackensack Meridian Health serves communities in northern New Jersey. Georgetown Lombardi is a member of the NCI Community Oncology Research Program (UG1CA239758). Georgetown Lombardi is supported in part by a National Cancer Institute Cancer Center Support Grant (P30CA051008). Connect with Georgetown Lombardi on Facebook (Facebook.com/GeorgetownLombardi) and Twitter (@LombardiCancer).