A new study identifies a protein known as angiopoietin-like 4 (ANGPTL4) as a driver of fibrosis (scarring) in diabetic kidney disease. The findings suggest that therapeutically targeting ANGPTL4 could prevent fibrosis before it develops—perhaps slowing the progression of a disease that commonly affects people with diabetes. For the roughly 30 million Americans diagnosed with diabetes, kidney disease has been shown to shorten life expectancy by as much as 16 years.
ANGPTL4 is a protein primarily involved in regulating fat metabolism. Previous literature has shown that individuals with higher levels of this protein are at greater risk of developing more severe diabetic kidney disease. However, scientists did not understand the mechanisms underlying this association.
To investigate, a Yale-led team developed novel animal models of diabetic kidney disease in which they knocked out ANGPTL4 in specific cell types in the kidney. When ANGPTL4 was turned off in these cells, the kidneys showed significantly less damage compared to models that contained the protein. When the researchers also treated diabetic mice with a therapy that reduced the expression of ANGPTL4, they found that this significantly reduced fibrosis. The team published their findings in Science Advances on December 4.
“This is the first time that tissue-specific ANGPTL4 has been shown to be pathogenic in diabetic kidney disease,” says Julie Goodwin, MD, associate professor of pediatrics (nephrology) and the study’s principal investigator.
For their study, Goodwin’s team engineered mice to have one of two common types of cells in the kidney—podocytes and renal tubular epithelial cells—to be deficient in ANGPTL4. Podocytes are specialized cells that play a critical role in filtering blood. Renal tubular epithelial cells, on the other hand, are involved in reabsorbing essential substances from the filtrate [fluid filtered from the blood]. “These two cell types make up about half of the cells in the kidney,” Goodwin says.
Then, the team induced diabetes in these mice to see how a lack of ANGPTL4 in either of the cell types affected the course of the diabetic kidney disease. They found that the engineered mice experienced less severe disease. “Interestingly, when we knocked ANGPTL4 out of either cell type, the animals were essentially protected from the progression of diabetes,” says Goodwin. “This indicates that this molecule is detrimental.”
ANGPTL4 associated with drivers of diabetic kidney disease
Intrigued, the researchers then explored the mechanisms underlying how ANGPTL4 drives diabetic kidney disease progression. So, in mouse models, they investigated how the protein interacted with different pathways that research has previously shown to drive the progression of diabetic kidney disease.
One such pathway is known as the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway. This pathway can be triggered by fragments of mitochondrial DNA released by damaged mitochondria, and once activated, it produces inflammatory molecules. The researchers found that ANGPTL4 deficiency in either the podocytes or renal tubular epithelial cells was associated with the downregulation of the STING pathway and less mitochondrial damage.
Fibrosis is also linked to impaired fatty acid oxidation, a biological process that is essential for energy production. “Research has shown that in the kidneys, in particular, when cells don’t have enough energy, those cells are more prone to getting shunted into a fibrosis pathway,” Goodwin explains. Her team found that the presence of ANGPTL4 was associated with the suppression of fatty acid oxidation.
The researchers also investigated how ANGPTL4 was associated with two other factors known to accelerate kidney fibrosis—the transforming growth factor beta (TGF-β) signaling pathway and a molecule known as dipeptidyl peptidase-4 (DPP-4). Once again, the team found that the protein was associated with the upregulation of TGF-β and elevated levels of DPP-4.
A potential therapeutic target
Finally, to evaluate ANGPTL4’s potential as a therapeutic target, the researchers treated diabetic mice with a kidney-specific antisense oligonucleotide (ASO). An ASO is a short strand of synthetic DNA or RNA designed to interfere with a target gene and prevent the production of a specific protein. The team found that an ASO designed to suppress ANGPTL4 significantly reduced fibrosis in mice with diabetic kidney disease. “This raises the question about whether this could be a targeted therapy for diabetic kidney disease,” says Goodwin.
As many as one in three people with diabetes have diabetic kidney disease, and the prevalence of the disease is growing globally. As diabetic kidney disease progresses, it can lead to kidney failure or the need for a kidney transplant. However, there are few effective therapies for preventing diabetic kidney disease and its progression, Goodwin says. “Examining the pathophysiology of the disease and trying to find novel molecules that influence progression is very important because the treatments that we have now are not ideal, and the number of people with diabetes is only getting bigger.”
Goodwin’s team is now exploring how ANGPTL4 affects other cell types in the kidney as well as its role in similar conditions such as nephrotic syndrome, a condition that causes too much protein to leak into urine. Her ultimate goal, she says, “is to leverage this work to develop a novel therapy that we can eventually use in a human population.”