Der Einfluss renaler Kristallablagerung auf die autosomal dominante Nierenzystenerkrankung (ADPKD)
Zusammenfassung der Projektergebnisse
Autosomal dominant polycystic kidney disease (ADPKD) represents one of the most common, monogenic diseases and is characterized by slow but relentless renal cyst growth leading to chronic kidney disease and ultimately requiring dialysis or kidney transplantation in most patients. It has been widely accepted that beside the single germ line mutation in one PKD gene (“First hit”) a random somatic mutation in the other allele (“Second hit”) has to occur to before any kind of kidney damage finally (“Third hit”) induce cystogenesis and set the pace of PKD disease progression. While several rare forms of renal injury were described as possible third hits9, the Weimbs Lab found a much more prevalent trigger: renal crystal deposition. Renal crystals occur daily in healthy humans and nephrolithiasis is very common in PKD patients. The Weimbs Lab showed that renal crystal deposition lead to reversible tubule dilation as a physiological reno-protective mechanism to clear renal crystals. They could show that the mTOR pathway, which is also pathologically activated in ADPKD, partially mediates this process and that renal crystal deposition can accelerate PKD disease progression in a heterologous animal model of PKD. This research project aimed to further characterize this proposed mechanism of reversible tubule dilation and to elucidate whether renal crystal deposition can not only accelerate but induce cystogenesis in a homologous PKD-1 model. Here we report, that not only mTOR signaling but also STAT6-signalling mediates reversible tubule dilation upon renal crystal deposition. While the STAT6 pathway is aberrantly activated in ADPKD, we found that STAT6 is also highly activated in tubule epithelial cells upon renal crystal deposition. Inhibition of STAT6 upon renal crystal deposition in mice, however, significantly reduces tubule dilation specifically in collecting ducts of the kidney and, thus, crystal clearance. This indicated that physiological STAT6 activation in tubule epithelial cells might be protective by facilitating renal crystal clearance while STAT6 over-activation as observed in ADPKD could trigger overdriving tubule dilation and, thus, cystogenesis. Furthermore, we report that primary cilia- non-motile antennae-like organelles- on renal epithelial cells are likely mediating the reversion process of tubule dilation upon renal crystal deposition. We initially found that renal crystal deposition led to a significant elongation of primary cilia in dilated tubules. Disruption of primary cilia, however, led to significantly increased tubule dilation and additionally cystogenesis. Those findings revealed for the first time, that primary cilia are not required for renal crystal deposition and tubule dilation. In contrast, the data indicates that cilia elongation upon renal crystal deposition might play an important role for renal tubules to return to normal diameters after crystal clearance. Finally, we investigated the impact of uric acid crystal deposition in a homologous Pkd1 rat model. Here we found that not only calcium-based nephrolithiasis but also uric acid crystals lead to reversible tubule dilation for crystal clearance. Thus, reversible tubule dilation might be a protective clearance mechanism independent of the type of crystal. Additionally, we report that uric acid crystal deposition not only accelerate disease progression of ADPKD but actually induces cystogenesis in a homologous heterozygous Pkd1+/- rat model that closely resembles human ADPKD. Those findings point rather towards a “Two-Hit” model of ADPKD where a germ-line mutation in a PKD gene followed by a trigger of kidney injury like renal crystal deposition is already sufficient to induce cystogenesis. This even more enforces the importance to control and prevent any kind of kidney injury in ADPKD patients. Because ADPKD patients have a high risk for nephrolithiasis, this data confirms the significance of renal crystal deposition in PKD disease progression and highlights the need to clinically treat risk factors facilitating renal crystal deposition in ADPKD.
Projektbezogene Publikationen (Auswahl)
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STAT signaling in polycystic kidney disease. Cell. Signal. 72: 109639, 2020
Strubl S, Torres JA, Spindt AK, Pellegrini H, Liebau MC, Weimbs T
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Ketogenic dietary interventions in autosomal dominant polycystic kidney disease—a retrospective case series study: first insights into feasibility, safety and effects. Clinical Kidney Journal sfab162, 2021
Strubl S, Oehm S, Torres JA, Grundmann F, Haratani J, Decker M, et al.
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Uric acid crystal deposition triggers reversible tubule dilation and cystogenesis in polycystic kidney disease, ASN Kidney Week, Orlando, USA, 2022
Strubl S, Holznecht N, Torres JA, Aceves B, Schimmel M, Asplund D, Kroes B, Arjune S, Harris P, Müller RU, Weimbs T
