The synthetic peptide appears to disrupt inflammation and protect the kidneys from nephritis

A synthetic peptide appears to directly disrupt the destructive inflammation that occurs in nephritis, allowing the kidneys to better recover and maintain their important functions, the researchers reported.

Whether they gave the peptide to the body scale or directly to the kidneys, it reduced the movement of immune cells in the kidneys, resolved inflammation and damage, and improved kidney function, without increase blood pressure, they report in the newspaper International kidney.

Things like a serious infection or injury, and diseases such as uncontrolled hypertension and diabetes, can cause acute or chronic nephritis, which affects both the kidneys and the one million filtering units of each. Patients, especially chronic, often suffer from kidney failure and dialysis, which pushes scientists and basic physicians to seek better interventions.

The researchers therefore administered the peptide in the same way that it could one day be administered to the patients, a few days after the inflammation of the kidneys. They discovered that this allowed an animal model of moderate nephritis to avoid characteristic problems such as excessive inflammation and protein in the urine, a sign of renal dysfunction, says Dr. Rudolf Lucas , a vascular biologist at the Vascular Biology Center of the Medical College of Georgia, Augusta. University.

Blood urea levels, a waste from the use of proteins by the body that should be eliminated by the kidneys, have also dropped, just like weight gain, primarily due to the retention of blood. Urine, which can also occur with kidney disease.

In a model mimicking a severe nephritis, which is essentially fatal for the kidneys in humans and lethal for the murine model, the mouse survival rate was 80%. "I think it is very promising," says Lucas, the corresponding author of the study.

In later stages of the disease, low doses of peptide also reduced the level of T cells, motor of the immune response and inflammation, moving in the region. In fact, the levels were essentially normal.

"The peptide actually seems to improve the kidney's overall condition over time," Lucas explains. In fact, he now wants to study whether the peptide can help restore chronic kidney disease, which many patients experience if their kidneys are not completely destroyed by nephritis.

According to them, the peptide, which has already been tested in Europe in patients with acute lung injury, such as pneumonia or trauma, and is also sought after in lung transplant patients, is promising for targeted treatment of acute nephritis. .

"We have shown that it reverses kidney inflammation during nephritis," says Dr. Michael Madaio, nephrologist, chairman emeritus of the MCG Department of Medicine and co-author of the author's author. study. "We showed that it was effective and that it was a local effect in the kidney itself."

Current therapies, such as corticosteroids, usually suppress the immune response, leaving patients at risk for infection and even cancer.

"We were looking for a great way to deal with this," said Madaio, whose lab developed the antibody that delivered the peptide directly to the kidneys. "In theory, it could replace the anti-inflammatory effect of steroids," says Madaio. "That would be great."

The TIP peptide developed by Lucas is a synthetic version of the advanced tumor necrosis factor, or TNF, which, as its name suggests, is known to target cancer. But TNF is also one of the main instigators of the destructive inflammation of nephritis.

In a mouse model of nephritis, they observed immune cells arriving in response to an attack by the kidneys – in this case a toxin – which in turn produced a lot of TNF. TNF then activated two main pathways promoting inflammation in the endothelial cells lining the one million renal filtering units, called glomeruli, in each kidney as well as in the podocytes, cells that envelop the tiny capillaries of the units filtering. The most important TNF-activated pathways in this case are p38 MAP kinase with NF-kB.

To make matters worse, TNF also decreased the production of elements such as nitric oxide, a potent dilator of blood vessels that could help the kidneys to recover, as well as prostaglandin E2, which can suppress the response. immune and inflammation.

"That's how high levels of TNF are bad for us, which means that urine has more protein and kidney inflammation increases, which is not what you want," Lucas says.

They would find that TIP peptide directly counteracts these negative changes.

"If we give the peptide TIP, we restore the basal rates," says Lucas about prostaglandin E2, which in turn induces nitric oxide. "So we are restoring two known factors to protect nephrotoxic nephritis," he said.

Although the most obvious route would be the direct suppression of TNF, this may not be a good idea because of its important role in the fight against infections and other invaders, which is already a concern for current treatments, they say.

"We think that a better approach could be factors that interfere with the deleterious signaling of TNF, which induces deep kidney inflammation, without interfering with the defense role of TNF against bacteria," Lucas says.

He discovered in the lungs that the peptide directly activates ENaC-alpha, a subunit of the body's natural channels that mediate the absorption of sodium and plays a role in the movement of fluids, Lucas explains, pointing to the natural propensity fluid to follow sodium or salt.

Although activation of the peptide by ENC-alpha in the lungs is a good thing in cases of pneumonia where the fluid interferes with breathing, investigators feared that ENaC-alpha activation in the kidneys would disrupt normal retention of sodium, which is important for the role of the kidney in regulating blood pressure.

Instead, they discovered that TIP peptide administered directly into the kidneys not only reduced inflammation, but also decreased blood pressure, even in the presence of a high-salt diet, without interfering with the anti-infectious role of TNF.

The inflammation of the kidney filtering units, called glomerulonephritis, is responsible for about 10 to 20% of patients' extensive renal injury, although the affected pathway is common to many forms of progressive kidney injury.

"Your kidneys just do not work as well as they do now," says Lucas. "Your glomerular filtration goes into the sewers, your body weight increases because you retain more urine.The TNF is a crucial mediator of this pathology."

TNF and another pro-inflammatory substance called interleukin 1, produce products such as reactive oxygen species that damage both the filters and the elastic cells that surround their exterior.

Lucas recently received a $ 2.5 million grant from the National Institutes of Health to deepen evidence that ENaC-alpha activation with its peptide can help eliminate the deadly accumulation of fluid in the lungs may occur during pneumonia. "It's a very different approach to working in the lungs," says Lucas about the new work in the kidneys.

"In the kidneys, the peptide directly interferes with one of the major causes of the problem, the p38," Lucas says, noting that p38 is known to play an important role in the cells lining the blood vessels and heart, and similar to those lining the glomeruli. .

Madaio was the corresponding author of a study this summer also in International kidney this showed that by using the same antibody, this time to directly deliver the anti-inflammatory protein kinase C-alpha inhibitor, allowed the recovery of the organ in a similar pattern of nephritis . They also found that kidney cells, called mitochondria, are particularly affected by acute and chronic inflammations and that the protein they provided restored mitochondrial function.

There are approximately one million filter units, called nephrons, in each kidney that remove waste, acid and excess fluid from the blood, which are excreted in the urine . Nephrons also return good substances, such as nutrients, to the blood. The glomerulus, a cluster of blood vessels inside the nephrons, functions as a filter.