We know that healthy people have living kidney cells, while dialysis patients have dead kidney cells. But what happens to kidney cells in chronic kidney disease patients during that transition from life to death?
Solving this mystery could help us prevent kidney cell death in patients.
Recent medical research has shed light on this critical process, so today we’ll explore an important pathway of kidney cell death: ferroptosis (iron-mediated cell death).
Iron: Essential Yet Dangerous
Everyone knows iron is essential for human health—anyone with iron deficiency wants to supplement it. But did you know that too much iron in the body is toxic?
(This is actually obvious—any substance becomes toxic in large doses. Even water can cause water poisoning. In medicine, we define toxicity as “excess equals poison.” Different substances just have different toxicity thresholds; those with very low thresholds we call poisons.)
When we consume iron, free iron ions cannot exist in large quantities alone. Instead, they bind with ferritin and ferritin complexes for safe storage.
When red blood cells say: “I need iron!” Ferritin responds: “Don’t worry, buddy, I’ll release some iron for you! Is that enough? I’ll store the rest safely so it doesn’t cause damage!”
In diseased kidneys, iron ions become excessive and toxic, causing kidney cells to undergo “ferroptosis.”
Medical scientists didn’t know ferroptosis existed until recently—they only knew about necrosis, apoptosis, and autophagy as cell death mechanisms.
In 2012, the prestigious journal Cell first reported the discovery of “ferroptosis” in human cells. Subsequently, kidney researchers discovered that kidney cells had been suffering from ferroptosis all along!
How Do Healthy Kidney Cells Undergo Ferroptosis?
Every type of chronic kidney disease involves cellular ischemia and hypoxia—whether from cell proliferation and edema compressing blood vessels, or blood vessel thickening, hardening, and narrowing.
For kidneys, oxygen deprivation is serious business. The kidney’s 2+ million nephrons all require energy to perform their filtering work. Remember learning about “mitochondria” in middle school biology? Mitochondria are the body’s “engines” that consume oxygen and produce energy.
Every movement we make requires mitochondrial power, including the process where ferritin binds with iron to form ferritin complexes and safely store iron. This energy-dependent process prevents free iron ions from becoming excessive and toxic.
But when kidneys become ischemic and hypoxic, mitochondria shut down. Iron can no longer be properly bound, resulting in large amounts of free iron ions. These “unemployed iron particles” accumulate and cause iron toxicity.
How do they cause damage? Large quantities of iron ions react with hydrogen peroxide, producing toxic byproducts called reactive oxygen species (ROS). ROS accumulation leads to kidney cell death.
The Ferroptosis Chain Reaction:
Kidney ischemia/hypoxia → Mitochondrial dysfunction/death → Excess free iron + hydrogen peroxide → ROS accumulation → Kidney cell death
Of course, ferroptosis involves several other pathways including lipid metabolism, amino acid metabolism, and immune inflammation. These pathways interact and intertwine to form a complex disease network. The mitochondrial pathway is just one typical branch of ferroptosis.
How Can We Block Kidney Cell Ferroptosis?
Since ferroptosis was discovered relatively recently, new disease mechanisms are still being uncovered. Many mechanisms likely remain undiscovered, so we don’t yet have miracle drugs.
Encouragingly, we’ve identified some medications that can improve ferroptosis to some degree:
Lip-1 is a ferroptosis inhibitor that blocks lipid peroxidation reactions, reducing hydrogen peroxide and ROS. Rather than directly reducing iron ions, it reduces iron’s “accomplices,” leaving iron isolated and unable to cause damage independently. This drug shows promise for future clinical kidney disease applications.
Already clinically available options include:
- Roxadustat, a recent anemia medication, which also has some ferroptosis-inhibiting effects
- Medications that improve kidney ischemia, addressing ferroptosis at its source:
- SGLT-2 inhibitors (dapagliflozin, empagliflozin, etc.) that reduce kidney cell oxygen consumption
- Traditional Chinese medicines that promote blood circulation, dilate blood vessels, and improve kidney blood flow and oxygenation (Salvia miltiorrhiza, safflower, zedoary, earthworm, etc.)
The Future of Ferroptosis Research
We hope kidney specialists will continue using their expertise to uncover more mysteries of kidney cell ferroptosis. As research deepens, more mechanisms, targets, and medications will be discovered, making greater contributions to kidney recovery for patients.
The discovery of ferroptosis represents a paradigm shift in understanding kidney cell death, opening new therapeutic avenues that could potentially slow or even reverse chronic kidney disease progression. While we’re still in the early stages of translating this knowledge into treatments, the future looks promising for patients struggling with kidney disease.
Important Note: This information is for educational purposes only. Any treatment decisions should be made in consultation with qualified healthcare providers who can assess your specific condition and medical needs.
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