A TRPC5 inhibitor has therapeutic benefits for progressive kidney disease, study finds


Potential treatment for progressive kidney disease

The kidneys are important organs in our bodies. The primary functions of the kidneys are to filter the blood and remove waste from the blood. In addition, the kidneys perform other important functions, such as regulating blood pressure, making red blood cells, and promoting healthy bones.

Progressive kidney disease refers to a condition in which kidney function is gradually lost. This disease is one of the most common causes of death in people. When progressive kidney disease develops to an advanced stage, it can affect almost every part of the body. For example, progressive kidney disease can lead to hyperkalemia, heart disease, weak bones, and swelling in your arms and legs. Current treatment for progressive kidney disease is limited, and more effective therapies are in need.

A lot of factors can increase a person's risk of developing progressive kidney disease. The most common causes of the disease are high blood pressure and diabetes. Many other illnesses such as glomerulonephritis, polycystic kidney disease, kidney stones, and urinary tract infections can also cause progressive kidney disease. Besides, some cases of progressive kidney disease are inherited.

According to a new study (A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models) published in the journal Science on 8 Dec. 2017, a team of researchers has demonstrated that TRPC5 activity is implicated in the pathogenesis of progressive kidney disease and blocking TRPC5 activity may represent a therapeutic strategy[1].

The study involves the collaboration among Harvard Medical School, Charles R. Drew University of Science and Medicine, University of Mississippi Medical Center, University of Nebraska Medical Center in the USA, University Heidelberg in the Germany, and several other research institutions. Dr. Anna Greka, an Assistant Professor at Harvard Medical School, is the corresponding author.

Persistent activation of many signaling pathways has been linked with progressive kidney disease. Some cases of progressive kidney disease are caused by genetic mutations that activate a protein called Rac-1, and accumulating evidence suggests that inhibition of Rac-1 may be an effective approach to treat progressive kidney disease.

For this work, the researchers found that Rac-1 activates another protein called TRPC5, which in turn destroys podocytes, cells critical for the kidneys' filtration function. To better elucidate the role of TRPC5 activity in the onset and progression of progressive kidney disease, the researchers tested a small molecule, AC1903, that could specifically block TRPC5 activity. They found that treatment with AC1903 prevented podocyte loss and restored kidney function in a transgenic rat model of progressive kidney disease. Experiments in a rat model of hypertensive proteinuric kidney disease also showed promising results.

Collectively, these data suggest that TRPC5 inhibitors like AC1903 may provide a novel treatment option for progressive kidney disease. Further, TRPC5 inhibitors may have therapeutic benefits for inherited as well as other forms of progressive kidney disease.


The kidneys

You have two kidneys in your body. The kidneys are bean-shaped, about the size of a fist, and located on the left and right in the back of the abdominal cavity.

The kidneys perform important functions, such as:

*Removing wastes from the food
*Maintaining overall fluid balance
*Regulating the body's salt content
*Regulating blood pressure
*Regulating pH Balance
*Producing hormones
*Processing Vitamin D

The kidneys are part of your urinary tract, the body's drainage system for removing urine. Other parts of the urinary tract include ureters, bladder, and the urethra.

Fig. 1 The Urinary Tract
Source: www.niddk.nih.gov

Healthy kidneys filter about a half cup of blood every minute. Blood comes into the kidney, waste gets removed, and salt and water are adjusted if needed. The filtered blood goes back into the body. Waste and extra water get turned into urine, which flows from the kidneys to the bladder through the ureters. Your bladder stores urine.


Progressive kidney disease

Progressive chronic kidney diseases affect more than 500 million people worldwide and are increasing in prevalence. These diseases are a type of kidney disease in which there is a progressive loss of kidney functions over a period of months or years. Current treatments usually do not alter the progression of disease and are associated with toxicities. Chronic kidney disease has become a serious public health issue. To reduce the economic burden of chronic kidney disease, it's critical to improve its prevention and treatment.

Risk factors

Many factors put you at risk of chronic kidney disease. Here is a list:

*Diabetes
*High blood pressure
*Mutations in genes such as UMOD (Uromodulin) and APOL1
*Being African-American, Native American or Asian-American
*Old age
*Obesity
*Smoking
*Polycystic kidney disease
*An infection
*Alcohol and certain drugs
*Systemic diseases like lupus
*IgA glomerulonephritis
*Heavy metal poisoning, such as lead poisoning
*Acute kidney injury
...

Among these causative factors, diabetes and high blood pressure are the most common.

Knowing these risk factors is critical for early intervention and prevention. For instance, maintaining a healthy body weight and avoiding smoking and excessive alcohol use may be good for the health of your kidneys[2][3].

Diagnosis

Your personal and family history will be helpful for the diagnosis of kidney disease. For example, having high blood pressure, having relatives who have kidney disease, and taking drugs that damage kidney functions may increase your likelihood of developing kidney disease.

Besides, there are several tests determine whether you have kidney disease, including:

1.Blood test

A blood test can measure the levels of a waste product called creatinine in your blood.  Your doctor can use the results of your blood creatinine test to calculate the glomerular filtration rate, which is the best to measure your level of kidney function and determine your stage of kidney disease.

2. Urine test

Urine tests tell your doctor if there is protein in your urine and how much albumin (a type of protein) and creatinine (a kind of waste) are in it. Using the results, your doctor can evaluate the filtering function of your kidneys.

3. Imaging test

There are different imaging techniques. The most commonly used imaging technique for in the diagnosis of kidney disease is ultrasound, which assesses your kidneys' structure and size. Sometimes, other imaging tests such as MRI are used.

4. Biopsy

A kidney biopsy involves taking a small piece of kidney tissue for laboratory analysis. The sample will be examined under special microscopes. The microscopes make it possible to see the samples in greater detail so that doctors could determine whether there are signs of damage or disease in your kidneys.

Complications

Over time, chronic kidney disease could lead to end-stage renal disease and increased cardiovascular morbidity and mortality. Progression of CKD is associated with a number of serious complications that affect almost every part of your body[4].

*Anemia
*Mineral and Bone Disorders
*Increased Cardiovascular Risk
*Dyslipidemia
*Nutritional issues
*Swelling
*High blood pressure
*Pulmonary edema
*Hyperkalemia
*Decreased sex drive, erectile dysfunction or reduced fertility, and pregnancy complications
*Damage to your central nervous system
*Decreased immune response
*Pericarditis
...

Treatment

Treatment of kidney disease depends on the specific cause. Although chronic kidney disease often has no cure, there are treatments that help control signs and symptoms, reduce complications or slow progression of the disease.

There are medications to treat high blood pressure, improve anemia, swelling, bone weakness, and other complications. In addition to therapeutic drugs, dietary modification is also an important treatment. For instance, A lower protein diet could help minimize waste products in your blood.

If chronic kidney disease progresses into end-stage kidney disease, there are other treatment options, such as dialysis and kidney replacement therapy. It's estimated that there are over 1.4 million patients receiving renal replacement therapy worldwide, causing a significant economic burden.


Reference:
[1] Yiming Zhou et al, A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models, Science (2017).
[2] William M. McClellan et al, Risk Factors for Progressive Chronic Kidney Disease, Journal of the American Society of Nephrology (2003).
[3] Rumeyza Kazancioglu, Risk factors for chronic kidney disease: an update, International Society of Nephrology (2013).
[4] Robert Thomas et al, Chronic Kidney Disease and Its Complications, Primary Care: Clinics in Office Practice (2008).
 

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