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Press release: Newly discovered mechanism in cystic kidneys

Project A2: Researchers at the University Hospital Erlangen have discovered a new mechanism for cyst growth in the familial cystic kidney disease ADPKD


July 9, 2024    Artikel auf Deutsch

ADPKD is one of the most common hereditary diseases worldwide and one of the main causes of loss of kidney function and thus dependence on renal replacement therapy such as hemodialysis or kidney transplantation. The cause is the formation of numerous cysts (fluid-filled cavities) in the kidneys, which increase in size over the course of a lifetime and thus displace healthy kidney tissue. Current therapeutic approaches to slow down the growth of cysts are only effective to a limited extent and are associated with relevant side effects.

Prof. Dr. Björn Buchholz, Senior Physician at the Medical Clinic 4 (Director: Prof. Dr. Mario Schiffer) at the University Hospital Erlangen, and his team have set themselves the task of deciphering the mechanisms of cyst growth. They have now been able to identify the purinergic receptor P2Y2R, which contributes significantly to cyst growth in an ADPKD mouse model. Both the silencing of the P2Y2R gene and the pharmacological inhibition by the drug suramin significantly improved the course of the disease. "One limitation is that suramin can also inhibit other purinergic receptors and is therefore not a suitable approach for long-term therapy. However, we are pleased that we have been in contact for some time with a leading pharmaceutical company that is very committed to developing a more specific active ingredient," explains Prof. Buchholz. He adds: "The fact that knocking out P2Y2R under physiological conditions showed no significant side effects even after more than a year and that P2Y2R was also detected at high levels in the cysts of our patients makes P2Y2R a promising pharmacological target."
The work was made possible by the German Research Foundation as part of the Transregional Renal Research Network Erlangen-Regensburg TRR 374. The results were published in the renowned scientific journal JASN

Original publication:
Andre Kraus, Kathrin Skoczynski, Martin Brötsch, Nicolai Burzlaff, Jens Leipziger, Mario Schiffer, Maike Büttner-Herold, Bjoern Buchholz: P2Y2R and Cyst Growth in Polycystic Kidney Disease. Journal of the American Society of Nephrology: 10.1681/ASN.0000000000000416, June 7, 2024. DOI: 10.1681/ASN.0000000000000416.

- TRR 374(https://www.uni-regensburg.de/biologie-vorklinische-medizin/sfb1350/crc-1350/index.html)
- AG Buchholz(https://www.medizin4.uk-erlangen.de/forschung/experimentelle-forschung/mechanismen-renalen-zystenwachstums/)

Further information:
Prof. Dr. med. Björn Buchholz
Phone: 09131 85-39002

Collaborative Research Center 1350 continues as Transregio 374

DFG funds joint UR and FAU collaborative research with 12.3 million euros

November 29, 2022

The proposal for the joint SFB/TRR 374 of the University of Regensburg (UR) with the Friedrich-Alexander-University Erlangen-Nuremberg (FAU) entitled "Tubular system and interstitium of the kidney: (Patho-) physiology and crosstalk" (formerly SFB 1350) has been approved by the German Research Foundation (DFG) for a 2nd funding period. Spokesperson is Prof. Dr. Richard Warth, Medical Cell Biology at the University of Regenburg. The total funding amount for the period from 2023 to 2026 is 12.3 million euros.

In Germany, more than 5 million patients suffer from chronic kidney disease - most of them without knowing it - and about 100,000 people require kidney replacement therapy in the form of dialysis or transplantation. For their detoxification and elimination function, the kidneys use a two-stage principle: First, a large amount of filtrate is formed from the blood plasma and then largely reabsorbed and modified in a system of tubules. Until now, research into kidney disease has focused mainly on the filtration process. The function of the tubules and the tissue surrounding them (tubulointerstitium) has hardly been studied, despite its great relevance to disease, because the interactions that take place there are exceedingly complex and methodologically difficult to address. Therefore, an interdisciplinary team of researchers has joined forces in the Renal Collaborative Research Center SFB 1350 / Transregio TRR 374 to investigate these complex processes and signaling pathways of the tubulointerstitium.

In the first funding period of the SFB 1350 from 2019-2022, the team of researchers from the University of Regensburg and the Friedrich Alexander University Erlangen-Nuremberg succeeded in gaining important insights into the development of various kidney diseases. For example, mechanisms of inflammatory processes and excessive scarring were uncovered and genetic risk factors for kidney function loss were identified.

For University President Professor Dr. Udo Hebel, the success of the Regensburg scientists is proof of the outstanding research work of the researchers involved in the SFB/TRR: "Excellent work is being done in the field of life sciences, and the extension that has now been approved is once again proof of the scientific excellence and, at the same time, the future viability of research in this field," said Prof. Hebel.

For the next funding period from 2023-2026, the research team's goal is to further deepen knowledge about the function and dysfunction of the tubulointerstitium of the kidney, to enable the development of new diagnostic and therapeutic strategies, and thus to prevent or delay the progression of kidney diseases.

From 2023, Collaborative Research Center 1350 will become Transregio 374, enabling the team led by Prof. Dr. Richard Warth, Prof. Dr. Frank Schweda, Prof. Dr. Kerstin Amann and Prof. Dr. Mario Schiffer will be able to even better combine basic research, clinical research, state-of-the-art technologies and data science, and further synergies can be created between the complementary eastern Bavarian kidney locations of Regensburg and Erlangen.

"The DFG's positive funding decision confirms our successful work and puts us, as Transregio 374, in an ideal position to shape modern kidney research together with national and international partners, train the kidney researchers and kidney doctors of the future, and develop tailored diagnostics and therapies for kidney disease patients," said Prof. Warth. "This success," Warth continued, "is also the moment to say thank you. The team of spokespersons would like to thank the researchers for their outstanding work and team spirit, but also especially for the great support from the two university administrations, the ministry and the colleagues of the research funding structures in Regenburg and Erlangen. In an ever tighter competition, in which a blink of an eye can make the difference, everyone involved has to pull together. This is the only way we were able to achieve this success."

DFG-GEPRIS webpage of TRR 374

Press release: New therapeutic approach for cystic kidneys

Projects A2 and A3: Research teams from Regensburg and Erlangen find a promising approach to the treatment of the familial cystic kidney disease ADPKD

August 28, 2020   Artikel auf Deutsch

"Cystic kidneys" are one of the most common inherited diseases worldwide, requiring dialysis in advanced stages. This is caused by the appearance of cysts (fluid-filled cavities) in both kidneys, which continuously increase in size and thus displace healthy tissue. The therapeutic options available to date are only very limited in their effectiveness and are accompanied by side effects. Researchers at the University of Regensburg and the University Hospital Erlangen have now shown in a comprehensive study that the chloride channel TMEM16A (anoctamine 1) contributes significantly to cyst growth and that pharmacological inhibition of TMEM16A significantly reduces cyst growth. This is achieved in part by two drugs already approved for other purposes in human medicine. The results have now been published in the journal Nature Communications.

About one in a thousand people suffer from the autosomal dominant polycystic kidney disease ADPKD, which in turn leads to irreversible loss of kidney function in about 50% of cases from the middle of the fifth decade of life. For patients, this means lifelong hemodialysis or kidney transplantation and a shortened life expectancy. In addition, those affected suffer from high blood pressure, pain and infections as a result of their kidney disease. It has been known for some time that continuous cyst growth is a major contributor to all these problems. The therapeutic options available to date have only very limited efficacy and are accompanied by relevant side effects.

An essential mechanism for cyst growth is the transport of fluid into the interior of the cysts. The research teams led by Professor Dr. Karl Kunzelmann and Professor Dr. Rainer Schreiber from the Institute of Physiology at the University of Regensburg and PD Dr. Björn Buchholz at the University Hospital Erlangen now report a potential breakthrough: Their research groups show that genetic inactivation of the chloride channel TMEM16A in an ADPKD mouse model led to a significant reduction in cyst growth. In a next step, they found that the highly specific pharmacological agent Ani9 achieved comparable inhibition of cyst growth. In their goal toward treating patients with renal cysts, they identified two promising compounds that suppressed cyst growth in mice and in cell experiments. These are benzbromarone, which has long been used to lower uric acid, and niclosamide, also an approved drug.

In their joint publication, the authors reveal the precise mechanism of action leading to cyst formation and its pharmacological inhibition: "Further studies are now needed to show good efficacy and tolerability in patients as well." In this context, the researchers refer to the Collaborative Research Center 1350 "Tubule System and Interstitium of the Kidney: (Patho-) Physiology and Crosstalk," in which they are involved with their research groups: "Collaborative Research Center 1350 offers us optimal conditions for conducting the experiments and for our close collaboration," Karl Kunzelmann and Björn Buchholz agree.

Original publication:
Ines Cabrita, Andre Kraus, Julia Katharina Scholz, Kathrin Skoczynski, Rainer Schreiber, Karl Kunzelmann, Björn Buchholz: Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo. In: Nature Communications.
DOI http://dx.doi.org/10.1038/s41467-020-18104-5

AG Kunzelmann © Prof. Dr. Karl Kunzelmann
Press release: Cystic fibrosis test to drink

Project A2: The role of a gene in the kidney allows a simple diagnostic method to be developed

July 29, 2020  Artikel auf Deutsch

Cystic fibrosis is primarily a severe lung disease, but it also affects other organs, such as the pancreas and intestines. Cystic fibrosis is caused by mutations in the so-called CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. This gene codes for a chloride channel that is typically found in organs that need to transport a lot of salt. The kidney is also such an organ. It is therefore all the more surprising that the kidney does not appear to show any functional impairment in the disease cystic fibrosis. The research teams led by Prof. Jens Leipziger in Aarhus/Denmark and from the Regensburg laboratory of the research duo Prof. Dr. Karl Kunzelmann and Prof. Dr. Rainer Schreiber have now made significant progress in understanding the role of CFTR in the kidney as part of Collaborative Research Center 1350.

CFTR is mainly found in specialized cells of renal tubules that help to adjust the pH of the blood. The paper by the Aarhus and Regensburg scientists, which has now been published in the Journal of the American Society of Nephrology, describes the precise cellular mechanism of pH regulation and the central role played by CFTR in this process. CFTR is activated by the digestive hormone secretin, which intervenes in a regulatory manner. One would now expect to find conspicuous changes in blood pH on a regular basis in cystic fibrosis patients. However, this is not the case, since other parts of the kidney and, above all, respiration are in the foreground in blood pH regulation in healthy people. However, an elevated pH, a so-called alkalosis, has been repeatedly reported in cystic fibrosis patients.

Currently, the diagnosis of cystic fibrosis disease is not straightforward because there are well over 2,000 different mutations. Current diagnostic procedures are either inaccurate, laborious, or burdensome and usually do not directly test CFTR function or residual function. The fact that cystic fibrosis patients cannot adequately regulate blood pH in the presence of alkalosis gave the researchers the idea of using this to diagnose cystic fibrosis: "The sick children or even older patients would simply have to drink a beverage that raises the blood pH for a short time. An increased pH value and the excretion of so-called bases could then be detected in the subsequently excreted urine," explains Prof. Leipziger. "If cystic fibrosis is present, this excretion would be absent," adds Prof. Kunzelmann. Precisely these findings have now been demonstrated in animal models of cystic fibrosis and in cystic fibrosis patients. Furthermore, the researchers were able to show that such a simple drinking test can be reliably used as a success control for therapy with recently developed CFTR repair drugs, so-called CFTR modulators. Such a simple test could also help save costs of the very expensive therapy. "As a next step, we are planning clinical trials to assess the everyday suitability of this simple and cost-effective cystic fibrosis test," the team is already looking ahead.

Original publication:
Peder Berg, Samuel L. Svendsen, Mads V. Sorensen, Casper K. Larsen, Jesper Frank Andersen, Soren Jensen-Fangel, Majbritt Jeppesen, Rainer Schreiber, Ines Cabrita, Karl Kunzelmann and Jens Leipziger: Impaired renal HCO3- excretion in Cystic Fibrosis, Journal of the American Society of Nephrology
DOI: https://doi.org/10.1681/ASN.2020010053

  1. Deutsche Forschungsgemeinschaft (DFG)
  2. Friedrich-Alexander Universität Erlangen-Nürnberg


"Interdisciplinary kidney research to advance understanding of disease mechanisms and develop new therapeutic concepts"


Dr. Michaela Kritzenberger
Tel.: ++49 (0)941/943-2885

Molecular Medicine