Researchers identify a source of kidney fibrosis, and a possible way to reverse it

Investigators working on two separate studies have determined that a protective cellular process—epithelial-to-mesenchymal transition (EMT)—also appears to be responsible for the development of renal fibrosis. The researchers also found evidence that inhibiting EMT could reverse renal fibrosis in humans. The two studies were published August 3 in Nature Medicine.

Approximately 40% of all deaths from kidney failure are due to fibrosis, and fibrosis accounts for the majority of lupus-related deaths. But no specific treatment is available for it, researchers explained.

A feature of kidney fibro­sis involves the transition of tubular epithelial cells (TECs) into cells with mesenchymal features—the process referred to as the epithelial-to-mesenchymal transition. But the exact role of the EMT of damaged TECs in renal fibrosis has been the subject of debate.

To determine the functional role of EMT in renal fibrosis, Raghu Kalluri, MD, PhD, and colleagues at the University of Texas MD Anderson Cancer Center in Houston, TX, generated mice in which two transcriptional regulators of EMT—Twist1 and Snai1—were deleted specifically in proximal TECs. They found that these mice, compared to similarly treated wild-type mice, maintained TEC integrity and had reduced EMT, which protected them from multiple renal insults, with less renal fibrosis and better renal function.

“The current study provides compelling genetic findings about that concept and new ideas for anti-fibrosis therapy,” Dr. Kalluri said. “It reveals that inhibition of EMT in TECs during chronic kidney injury represents a potential anti-fibrosis therapy. It would be a significant advance in how this illness is treated and could potentially save many lives.”

In a separate study, M. Angela Nieto, PhD, professor and head of the Developmental Neurobiology Unit at the Instituto de Neurociencias, in Alicante, Spain, and colleagues, demonstrated that TECs undergo only a partial EMT in response to renal injury. They found that EMT doesn’t directly generate interstitial myofibroblasts, but instead induces signals that stimulate myofibroblast differentiation and inflammation.

To investigate whether they could reverse fibrosis, Dr. Nieto and colleagues inactivated Snai1 expression in mice. They found that this approach ameliorated fibrosis and reduced inflammation in treated mice.

“Our data show that fibrosis can be reversed, and support the use of anti-Snail1 and anti-EMT therapeutic strategies for the treatment of fibrosis,” Dr. Nieto said. “Further studies need to determine the point at which fibrosis can no longer be reversed by Snai1 inhibition."

Dr. Kalluri added, “These two studies refute the misconception that EMT is of no functional consequence to kidney dysfunction."