How ACE2 Receptors in Kidneys May Explain COVID-19-Related Kidney Damage

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How ACE2 Receptors in Kidneys May Explain COVID-19-Related Kidney Damage

When the World Health Organization (WHO) declared COVID-19 a global public health emergency in 2020, doctors quickly noticed an alarming pattern: even though the virus primarily attacks the lungs, many patients—especially those in intensive care—developed acute kidney injury (AKI), a sudden loss of kidney function. A 2020 study by researchers at the Chinese People’s Liberation Army (PLA) General Hospital offers a critical clue: the same receptor that lets COVID-19 enter lung cells—angiotensin-converting enzyme 2 (ACE2)—is also abundant in kidney tissue.

What Is ACE2, and Why Does COVID-19 Care?

ACE2 is a protein found on the surface of cells in several organs. Its normal job is to regulate blood pressure by breaking down angiotensin II, a hormone that narrows blood vessels. But for COVID-19 (formally called 2019-nCoV), ACE2 is a doorway. The virus’s spike protein binds to ACE2, and another enzyme—transmembrane protease serine 2 (TMPRSS2)—cuts the spike protein to allow the virus to fuse with the cell membrane. Without both ACE2 and TMPRSS2, the virus can’t infect cells.

The Study: Mapping ACE2 and TMPRSS2 in Kidneys

To understand if kidneys are vulnerable to COVID-19, the PLA General Hospital team (led by Yi-Yao Deng, Ying Zheng, Guang-Yan Cai, Xiang-Mei Chen, and Quan Hong) used single-cell RNA sequencing—a cutting-edge technique that tracks gene activity in individual cells. They analyzed data from three sources:

  • Healthy adult kidneys (from the Gene Expression Omnibus, or GEO, database: accession numbers GSE109564 and GSE114156).
  • Tumor-adjacent kidney tissue (from three patients with kidney tumors, GEO accession GSE131685).
  • Fetal kidneys (from 8–18-week-old embryos, via the Kidney Interactive Transcriptomics, or KIT, database: http://humphreyslab.com/SingleCell/).

To confirm their findings at the protein level (since gene activity doesn’t always equal protein presence), they used the Human Protein Atlas (https://www.proteinatlas.org), a public database of protein expression in human tissues.

Key Finding: ACE2 Lives in Kidney Tubules

The results were clear:

  • ACE2 was most active in the proximal tubules—the part of the kidney that reabsorbs water, glucose, and nutrients from the blood. This was true for healthy adults, tumor-adjacent tissue, and even fetal kidneys (where ACE2 was found in “tubular precursors,” the cells that become mature tubules).
  • TMPRSS2 was present in the loop of Henle (which balances salt and water) and collecting ducts (which carry urine to the bladder).

For context, ACE2 was not highly expressed in normal lungs—only low levels were found in lung macrophages. This helps explain why COVID-19 primarily causes respiratory symptoms but can still harm kidneys: the virus’s entry tools are concentrated in kidney tissue.

Why This Matters for COVID-19 Patients

Since COVID-19 relies on ACE2 and TMPRSS2 to infect cells, the study suggests kidneys are a direct target of the virus. This aligns with real-world data:

  • 7% of early COVID-19 patients developed AKI, rising to 31% in ICU cases (Huang et al., The Lancet, 2020).
  • 11 of 59 patients had elevated plasma creatinine (a marker of kidney stress) as the disease progressed (Li et al., medRxiv, 2020).
  • 4.3% of severe cases had increased creatinine (Guan et al., New England Journal of Medicine, 2020).

This pattern isn’t unique to COVID-19. The 2003 SARS virus (SARS-CoV) also used ACE2 and caused AKI in 6.7% of patients—with a 91.7% mortality rate for those with kidney injury (Chu et al., Kidney International, 2005). MERS-CoV, another coronavirus, used a different receptor (DPP4) but still caused AKI in 26.7% of patients. DPP4, like ACE2, is found in kidney tubules.

What This Means for Care and Treatment

The study’s findings have two critical implications for COVID-19 patients:

  1. Monitor kidney function closely: Patients with elevated plasma creatinine, protein in urine, or high blood urea nitrogen (another kidney marker) should be watched carefully. Early intervention—such as continuous renal replacement therapy (a type of dialysis)—can preserve kidney function and save lives.
  2. Target ACE2/TMPRSS2 for treatments: Drugs that block ACE2, TMPRSS2, or the virus’s spike protein could prevent COVID-19 from infecting kidney cells. While no such treatments are yet approved for COVID-19, this research gives scientists a clear path forward.

The Big Picture

The PLA General Hospital study doesn’t just explain why COVID-19 harms kidneys—it gives doctors and researchers a roadmap for protecting one of the body’s most vital organs. By focusing on the ACE2 and TMPRSS2 proteins, we can move beyond treating kidney damage to preventing it.

doi.org/10.1097/CM9.0000000000000783

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