HSS Scientists Identify Key Regulator of Pathways Linked to Kidney Damage in Lupus

Researchers at the Hospital for Special Surgery (HSS) and their colleagues found that inactivating the protein, called iRhom2, prevented kidney injury in mice vulnerable to developing lupus. Particularly promising, according to the researchers, is that the kidneys of mice lacking the iRhom2 gene were shielded by both a reduction in general inflammation and the prevention of irreversible scarring of the organs -- a powerful two-for-one effect.  

"A mechanism to block or inhibit iRhom2 would inhibit two key pathways for renal injury in patients with lupus without significant side effects," said Jane Salmon, MD, Collette Kean Research Chair and Senior Research Scientist at the Hospital for Special Surgery, and Professor of Medicine at Weill Cornell Medicine, who led the study in collaboration with Carl Blobel, MD, PhD, the V. F. and W. R. Salomon Chair in Musculoskeletal Research and Director of the Arthritis and Tissue Degeneration Program at HSS and Professor of Medicine at Weill Cornell Medicine.

The researchers reported their findings in the March 5th issue of the Journal of Clinical Investigation.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects an estimated 1.5 million people in the United States. The condition frequently leads to severe and potentially lethal damage to a variety of organs including the skin, brain, lungs, heart and kidneys. Women are roughly 10 times more likely than men to develop lupus.

Kidney damage from lupus, called lupus nephritis, affects between 40% and 60% of adults with SLE. Injury to this organ, which filters waste from the bloodstream and helps regulate blood pressure, involves the gradual accumulation of molecules called immune complexes. These clusters trigger inflammation that can lead to irreversible scarring and eventual failure of the organ. Patients with kidney failure must undergo regular dialysis until a transplant is available.

Over the past 20 years, researchers have identified several proteins that contribute to chronic kidney disease. One of these, a disintegrin and metalloprotease 17 (Adam17), acts like a pair of molecular scissors on the surface of cells. Its job is to clip off, or shed, substances that act as signals to other cells. Among these signaling molecules are a potent driver of inflammation called tumor necrosis factor-alpha (TNF-a), and heparin-binding epidermal growth factor (HB-EGF), a protein that helps maintain the skin and intestinal integrity.      

However, in autoimmune diseases such as lupus, HB-EGF is directly linked to irreversible scarring, or fibrosis, of kidney tissue, while having too much TNF-a marshals the immune system to wage perpetual war against the body itself by activating inflammatory cells to attack the organs.

Scientists have tried inhibiting Adam17 in the hopes of reducing or eliminating the excessive shedding of TNF-a that leads to tissue injury in autoimmune illnesses. But Dr. Salmon points out that Adam17 is involved in so many processes – including essential functions such as keeping the skin and gut protected against microbial invaders – that blocking it could prove catastrophic.

In earlier work, Dr. Blobel and colleagues found that iRhom2 and a related gene, iRhom1, control the expression of Adam17. "They separate out the protective and pro-inflammatory functions of the gene. iRhom2 is meant to immediately respond to bacterial invaders by activating Adam17, which tells cells to release defensive substances (TNF-a) and strengthen the integrity of the skin and intestines by releasing HB-EGF," he said. "If you have a breach of the barrier, you want to do two things: You want to rebuild the barrier and you want to activate the immune system."

For the new study, the HSS investigators sought to learn if they could ratchet down Adam17 by manipulating iRhom2. "In patients with lupus nephritis, you see an increase in expression of iRhom2," Dr. Salmon said. "But if you have more iRhom2, you have more Adam17, and therefore more shedding of TNF-a and HB-EGF."

Xiaoping Qing, MD, PhD, an Instructor in Autoimmunity and Inflammation Program studied a strain of mice with a mutation that predisposes them to lupus and kidney injury. Blocking iRhom2 prevented the organ damage. Analysis of the kidney tissue showed greatly reduced inflammation, scarring and other signs of harm.

The researchers also treated the same strain of mice either with a drug that suppresses the activity of TNF-a or a drug that blocks signaling by the receptor for HB-EGF, the EGFR. Treated animals showed significantly less evidence of kidney damage than untreated rodents, indicating that TNF-a and the EGFR play important roles in the disease process of lupus.

Using tissue samples from kidney biopsies, they found that elevated expressions of HB-EGF with the highest levels are associated with irreversible damage. In addition, exploring data from a large national databank revealed that kidney cells from patients with lupus express abnormally high amounts of iRhom2, another indicator of the role of this molecule in the development of lupus nephritis.

The findings are particularly promising, the researchers added, because despite hitting two extremely important molecular pathways at the same time, blocking iRhom2 appears to be quite safe. "From a medical point of view, that's what makes this approach so attractive," Dr. Qing said. "Nobody can find anything wrong with mice that have no iRhom2, but they seem to be protected from autoimmune diseases."

In future research, the HSS team hopes to test various methods of suppressing iRhom2.

About HSS l Hospital for Special Surgery
HSS is the world's leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the eighth consecutive year) and No. 3 in rheumatology by U.S. News & World Report (2017-2018).  Founded in 1863, the Hospital has one of the lowest infection rates in the country, and was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center four consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State. In 2017 HSS provided care to 135,000 patients from 80 countries, and performed more than 32,000 surgical procedures.  In addition to Patient Care, HSS leads the field in research, innovation, and education.  The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair, and tissue regeneration.  The HSS Innovation Institute was formed in 2015 to realize the potential of new drugs, therapeutics and devices; the global standard total knee replacement was developed at HSS in 1969, and in 2017 HSS made 130 invention submissions (more than 2x the submissions in 2015). The HSS Education Institute provides continuing medical curriculum to more than 15,000 subscribing musculoskeletal healthcare professionals in 110 countries.  Through HSS Global, the institution is collaborating with medical centers worldwide to advance the quality and value of care, and to make world-class HSS care more accessible to more people.

SOURCE Hospital for Special Surgery

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