Kidney disease: Cilia in the spotlight

 Chronic kidney diseases are the tenth leading cause of death worldwide. While some cases are linked to diabetes, toxin exposure or high blood pressure, other forms of the disease – termed polycystic kidney diseases (PKD) – are genetic and represent some of the most common inherited diseases in man. These potentially fatal disorders can manifest at any time from early childhood to late adulthood, and are characterised by cysts, inflammation and fibrosis of the kidney. Intriguingly, PKD is linked to mutations affecting a ubiquitous but oft-overlooked cellular structure termed the primary cilium. Accumulating evidence suggests that cilia act as antennae that sense a plethora physical and chemical stimuli and trigger intracellular signalling pathways. However, the molecular mechanisms linking defective cilial function to kidney inflammation and disease have remained enigmatic. A research team led by nephrologist and BIOSS Associate Prof. Dr. med. Wolfgang Kühn has now provided insight into this important question.

The researchers focused their attention on a protein called LKB1. Recent studies have implicated LKB1 in signalling pathways triggered by the bending of cilia. By deleting the gene encoding LKB1 specifically in cells of the kidney, Kühn and colleagues observed that LKB1-deficiency in mice recapitulates the inflammatory hallmarks of PKD including enhanced production of a protein called CCL2 that attracts inflammatory immune cells. In contrast, mice with kidney cells that lack primary cilia failed to produce CCL2 and were protected from PKD. Together, these results suggested that cilia transmit a signal that activates CCL2 production by kidney cells and therefore instigates inflammation, and that LKB1 may negatively regulate this signalling pathway. In order to elucidate the molecular mechanisms explaining these results, the team used a proteomic screen to determine the proteins that interact with LKB1 in kidney cells. Interestingly, these experiments identified a protein complex composed of several cilial proteins that have been previously linked to PKD, and also several novel interactors of LKB1. To determine whether the protein complex they discovered regulates the cilial pathway that promotes inflammation, the authors disrupted the complex by blocking the expression of different components of the complex. The observation that cells without LKB1 and its interaction partners produced much more CCL2 suggests this newly discovered LKB1 protein complex acts as a gatekeeper of inflammatory pathways that drive PKD.

Currently, there are no FDA-approved treatments for PKD. In Europe and Japan the antidiuretic hormone antagonist Tolvaptan has been approved for the most prevalent form of PKD, autosomal dominant PKD (ADPKD), but is limited in its use due to side effects. The only other available options at advanced disease stages are dialysis and – given a matching donor kidney – transplantation. Fundamental research on the mechanisms regulating inflammation in the kidney, including the ongoing studies in the Kühn group, may pave the way for the development of novel treatments for PKD and potentially other chronic kidney diseases.

Original Publication:

Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney
Viau A, Bienaimé F, Lukas K, Todkar AP, Knoll M, Yakulov TA, Hofherr A, Kretz O, Helmstädter M, Reichardt W, Braeg S, Aschman T, Merkle A, Pfeifer D, Dumit VI, Gubler MC, Nitschke R, Huber TB, Terzi F, Dengjel J, Grahammer F, Köttgen M, Busch H, Boerries M, Walz G, Triantafyllopoulou A, Kuehn EW.
EMBO J. 2018 Jun 19. [Epub ahead of print]

http://emboj.embopress.org/content/early/2018/06/19/embj.201798615.long

Contact

Prof. Dr. Wolfgang Kühn

Renal Department

Medical Center – University of Freiburg

Tel: +49 761 270 32270

E-mail: wolfgang.kuehn@uniklinik-freiburg.de

Further Information:

Kühn Lab Homepage: http://www.nephrolab.org/groups/wolfgang-kuehn/

Kidney Donation:  www.uniklinik-freiburg.de/medizin4/