| | |  | | NEWSLETTER ::: NO. 18 ::: JULY 2019 | | SUFFOCATING KIDNEY FIBROSIS | | Kidney injury can result in fibrosis, an excessive scarring of the tissue, which leads to a progressive loss of renal function. Recent research suggests that inhibition of cellular oxygen sensors is a novel therapy option for kidney fibrosis. | To this day there is no cure for kidney fibrosis. In the event of excessive formation of scar tissue (fibrosis) as a result of kidney injury current treatments can at best delay the process. Fibrosis ultimately leads to a progressive loss of renal function and can even result in kidney failure. Current research shows that inflammatory and fibrotic processes are regulated by oxygen deprivation. This regulation may be utilized to protect renal tissue against fibrosis.
|  | |
OXYGEN AND FIBROSIS - A COMPLEX RELATIONSHIP
Oxygen is essential for human life, fuelling cells’ energy production. If the available oxygen is decreased so that cellular energy production is affected, the condition is called hypoxia. All cells in the human body can sense decreases in oxygen levels. When hypoxia occurs, cells change their energy production, switching to an oxygen-independent, but less efficient, mechanism. The interaction between fibrosis and hypoxia is complex. On the one hand, fibrosis can cause hypoxia, as in when - for example - excessive scar tissue hinders oxygen delivery to the injured site.
Fibrotic tissue is in fact often hypoxic. On the other hand, hypoxia can regulate fibrosis, but the details of this regulation are still largely unclear. Both acceleration and dampening of fibrosis by hypoxia have been reported. This likely depends on the context of the underlying disease or tissue injury. However, the hypoxia - fibrosis interplay is thought to play an important role in the development of chronic kidney disease (CKD) after acute renal injury.
A BREATH OF FRESH AIR FOR RENAL FIBROSIS TREATMENT
Cellular oxygen sensors, called PHDs and FIH, are the main proteins responsible for the adaptation of cells to hypoxia. Given the described detrimental role of hypoxia following renal injury, it may seem unreasonable to target cellular oxygen sensors as a treatment option for renal fibrosis. However, many previous investigations have demonstrated that the exposure of tissue/organs to hypoxia or to chemicals that mimic hypoxia has tissue-protective effects. Hence, inhibiting cellular oxygen sensors is protective. The mechanisms behind this effect are not very well understood, but there are likely several different ones.
For example, using a chemical inhibitor will target all cells within the kidney. This may render healthy tissue areas more inert to a possible subsequent fibrotic impact and prevent the spreading of the hypoxic scar tissue. Furthermore, chemical inhibitors will lead to a strong or even complete inhibition of cellular oxygen sensors, while in contrast the distribution of oxygen in the diseased kidney will follow a gradient (the closer to blood vessels the higher the levels) and lead to a highly variable inhibition within fibrotic tissue.
JUNIOR GRANT ENABLES RESEARCH
While chemical inhibition of cellular oxygen sensors may be a promising and novel treatment option for preventing fibrotic remodelling during CKD, a more detailed understanding of the underlying mechanisms leading to the protective effect is necessary before such inhibitors may be used on patients.
A Junior Grant from Kidney.CH is enabling me to investigate a possible mechanism contributing to this protective effect. It furthermore allows me to supervise my own PhD student and to prove myself as an independent scientist. The transition from a researcher working for a supervisor to supervising someone yourself is difficult, and a bottleneck in academic research. The Junior Grant offers a great opportunity to efficiently bridge this transition. If the Junior Grant period is successful, I will be able to compete for larger funding, which is often otherwise a limiting factor in the development of an independent research career. In addition, the network of the Kidney.CH provides a unique basis for collaboration, which in turn contributes to a successful Junior Grant period. It enabled me (working in Zurich), for example, to establish a collaboration with CKD experts at the University of Geneva. Therefore, Kidney.CH and its Junior Grants offer an exceptional framework and opportunity for young scientists to drive their ideas independently, while benefitting from this large network of leading Swiss kidney experts.
|  | | | Visualization of components of the tissue scaffold (dark red colour) in a healthy mouse kidney and during fibrosis. | | WHAT IS FIBROSIS? | | When tissues and organs are injured, a highly coordinated healing process is set in place to achieve functional recovery. This process involves the removal of damaged tissue, the expansion of cells to replace missing or non-functional tissue, and the guidance of expanded cells into the correct place, as well as keeping the cells in the necessary position. Each of these steps has to be properly controlled and stopped in time. If this fails, an excessive “tissue repair” ensues, leading to uncontrolled scar formation and further tissue destruction, which ultimately could destroy the entire organ. This excessive tissue repair is called fibrosis. Renal fibrosis can eventually lead to kidney failure. | | Carsten Scholz is senior associate scientist at the Institute of Physiology of the University
of Zurich, is a Junior Grant Awardee of the NCCR Kidney.CH.
Before coming to Zurich, he completed his PhD in Translational Medicine at the Conway Institute of University College Dublin in Ireland and worked as a postdoc at Systems Biology Ireland. His research focuses on oxygen-dependent regulations in physiology and disease. |
|
| | | | Kidney - Control of Homeostasis | | is a Swiss research initiative, headquartered at University of Zurich, which brings together leading specialists in experimental and clinical nephrology and physiology from the universities of Bern, Fribourg, Geneva, Lausanne, and Zurich, and corresponding university hospitals. |
| | |
| |
|