Kidney Damage: New Insights into Initiation, New Targets for Therapy
Multiple recent studies have provided important insights into the origin of scar tissue that is seen in some forms of kidney disease.
“Fibrosis”—the term that describes the deposition of large amounts of collagen-rich connective tissue that can lead to organ damage—is seen in many conditions related to inflammation and, unchecked, can diminish the ability of an organ to perform its normal functions. In the kidney, fibrosis is a common final pathway for many diseases. It may arise as the result of a brief, severe injury to the kidney—causing acute kidney failure—or from a slowly-progressing, chronic condition. Extensive kidney fibrosis, and the scar tissue that can sometimes arise, can impair the removal of toxins and excess fluid from the blood, cause irreversible organ damage and, in severe cases, lead to kidney failure. New reports shed more light on the origins of kidney fibrosis and identify multiple potential new targets for therapy.
One study focused on molecular regulators of gene expression (the extent to which gene functioning is on or off), and how these regulatory factors might influence the deposition of fibrous tissue following kidney injury. In this study, researchers examined two different mouse models of kidney fibrosis, and sought to identify regulators of gene expression that were elevated in the presence of scarring. The researchers focused on one molecule, microRNA 21 (miR-21) that was found to be highly elevated in two mouse models of kidney disease soon after injury but before fibrosis appeared. This molecule is also found in humans with kidney injury. Mice engineered to lack the miR-21 gene showed diminished fibrosis in response to kidney injury; similar results were observed in normal mice that had been treated with an inhibitor of miR-21. This molecule represents a potential target for antifibrotic therapies in kidney disease.
Another research group identified a cell surface protein, activin-like kinase 3 (Alk3), that is present at elevated levels following kidney injury. Deletion of this protein in certain areas of the kidney leads to increased fibrosis, suggesting that it plays a protective role in the organ. The scientists developed a small, synthetic protein that bound to and activated Alk3. This agent suppressed inflammation and reversed established fibrosis in five different mouse models of kidney disease. Molecules such as this synthetic protein may be able to treat, and possibly reverse, kidney fibrosis.
Two other studies investigated the role of various cell types within the kidney, and tried to identify the source of the collagen-producing cells that can lead to fibrosis. One focused on pericytes, a type of stem cell that is usually associated with blood vessels, in kidney injury and fibrosis. Previous research indicated that kidney fibrosis appears to arise through a pathway involving cells derived from pericytes. The current study found that kidney pericytes increased their levels of the enzyme ADAMTS1, which plays a role in remodeling the tissue surrounding kidney cells, and downregulated an inhibitor of this enzyme, TIMP3, following kidney injury. Mice engineered to lack TIMP3 were more susceptible to kidney injury-induced fibrosis. Together, these results suggest central roles for regulators of enzymes that can modify networks of blood vessels in the kidney following injury.
In a second project focused on the role of a particular type of kidney cell, scientists used a new mouse model to study acute kidney injury and fibrosis. This study involved selective injury to the proximal convoluted tubules, which are part of the nephron, the basic structural and functional unit of the kidney. These tubules resorb about two-thirds of the fluid generated by the glomeruli, the filtering units within the kidney’s nephrons. After inducing a one-time injury in a specific region of these tubules, the scientists observed the proliferation of tubular cells and the appearance of inflammatory cells. Following this single injury, the kidney recovered completely. However, when the researchers induced three injuries at one-week intervals, they observed diminished cellular repair, with resultant blood vessel damage and fibrotic damage to both the kidney tubules and the glomeruli. This study shows that repeated injuries, even to only a portion of the nephron, can lead to more widespread kidney damage, similar to that associated with chronic kidney disease.
Researching another form of kidney disease, a team of scientists used computational and systems biology approaches to examine signaling molecules that regulate gene expression in a mouse model of HIV-associated kidney disease. They identified the protein HIPK2 as a key regulator of kidney fibrosis. Levels of this protein were found to be elevated in both the mouse model and in patients with various forms of kidney disease. Deletion of the gene encoding HIPK2 in the mouse model improved kidney function and reduced the severity of fibrosis. HIPK2 may be a potential target for novel therapies to address kidney fibrosis.
These five studies illuminate the complex system of regulation surrounding kidney fibrosis following injury, and identify multiple potential targets for further strategies aimed at preventing and possibly reversing kidney fibrosis, thereby preserving kidney function. Understanding the cellular and molecular mediators of kidney fibrosis is a high priority for scientists studying kidney disease. The identification of the factors that play a key role in this process might identify new targets for treatment aimed at preventing or reversing fibrosis. Furthermore, a better understanding of fibrosis in general could yield insights into how this process unfolds in other tissues and organs, potentially opening up new avenues to therapy for a range of diseases.