Loss of Polycystin-1 causes cAMP-dependent switch from tubule to cyst formation

Scholz, Julia Katharina; Kraus, Andre; Lüder, Dominik; Skoczynski, Kathrin; Schiffer, Mario; Grampp, Steffen; Schödel, Johannes; Buchholz, Björn

doi:10.1016/j.isci.2022.104359

Cited by 8 publications

(7 citation statements)

References 48 publications

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“…Mutations in PKD1 or PKD2 alter renal tubular mechanosensation and disrupt intracellular calcium homeostasis (5, 6). This results in increased levels of cyclic adenosine monophosphate (cAMP) (7, 8), dysregulated epithelial cell proliferation (9, 10), ion secretion (11) and cyst formation. Current drugs for ADPKD are directed towards the kidney epithelium.…”

Section: Introductionmentioning

confidence: 99%

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

Jafree,

Perera,

Ball

et al. 2024

Preprint

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Hallmarks of autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney anomaly, include expanding fluid-filled epithelial cysts, inflammation, and fibrosis. Despite previous work showing the potential of vascular-based therapies, renal microvascular alterations in ADPKD, and their timing, are poorly understood. Using single-cell transcriptomics of human kidney microvasculature, we identify a population of endothelial cells adjacent to cysts in ADPKD. This pericystic endothelium, distinguishable by its expression of osteopontin (SPP1), has a distinct molecular profile compared to the common endothelial cell injury signature in other kidney diseases. SPP1+ pericystic endothelium was also present in an orthologous mouse model of ADPKD before overt kidney functional decline. By interrogating geometric, topological and fractal properties from three-dimensional imaging of early ADPKD mouse kidneys, we show that pericystic endothelium associates with disorganisation and non-uniformity of the renal cortical microvasculature. Concurrently, we detected region-specific reductions in cortical blood flow within ADPKD murine kidneys using arterial spin labelling. We conclude that ADPKD kidneys contain a unique subset of endothelium manifesting with aberrant remodelling and impaired blood perfusion. Its detection, prior to renal functional decline, advocates the vasculature as a therapeutic target to modulate or preserve renal function in early ADPKD.

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Section: Introductionmentioning

confidence: 99%

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

Jafree,

Perera,

Ball

et al. 2024

Preprint

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“…Reduced polycystin function is thought to cause dysregulation of intracellular calcium, activation of adenylyl cyclases 5 and 6, inhibition of phosphodiesterase 1, and upregulation of cAMP and PKA signaling (Gattone et al, 2003;Torres et al, 2004;Wang X et al, 2005;Wang et al, 2008;Aihara et al, 2014). Upregulation of cAMP and PKA signaling may to a large extent be responsible for the disruption of tubulogenesis and initiation of cystogenesis (Song et al, 2003;Gallegos et al, 2012;Scholz et al, 2022) and for the progression of the cystic disease by stimulating fluid secretion (Sullivan et al, 1998;Grantham, 2003) and, in the setting of reduced intracellular calcium, epithelial cell proliferation (Yamaguchi et al, 2003;Yamaguchi et al, 2004;Yamaguchi et al, 2006). Previous studies have shown that constitutive activation of PKA not only causes a marked aggravation of PKD in mice with a hypomorphic Pkd1 mutation but also induces a cystic phenotype in mice with a wild-type genetic background (Ye et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of constitutively active PKA catalytic subunits can also act as a Frontiers in Molecular Biosciences frontiersin.org negative regulator of planar cell polarity signaling and block convergent extension during Xenopus gastrulation (Song et al, 2003). Deletion of polycystin-1 increased cAMP and switched tubule formation by principal-like MDCK cells to cyst formation, and pharmacological elevation of cAMP in polycystin-1competent cells caused cyst formation, impaired plasticity, nondirectional migration, and mis-orientation strongly resembling the phenotype of polycystin-1-deficient cells (Scholz et al, 2022). Mis-orientation of developing tubule cells in metanephric kidneys upon loss of polycystin-1 was also phenocopied by pharmacological increase of cAMP in wildtype kidneys.…”

Section: Cyst Initiationmentioning

confidence: 94%

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling

Zhou

Torres

2022

Front. Mol. Biosci.

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Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes shared by many other diseases. Dysfunction of the polycystins, encoded by the PKD genes, is closely associated with disruption of calcium and upregulation of cyclic AMP and protein kinase A (PKA) signaling, affecting most downstream regulatory, signaling, and pathophysiologic pathways altered in this disease. Interventions acting on G protein coupled receptors to inhibit of 3′,5′-cyclic adenosine monophosphate (cAMP) production have been effective in preclinical trials and have led to the first approved treatment for ADPKD. However, completely blocking cAMP mediated PKA activation is not feasible and PKA activation independently from cAMP can also occur in ADPKD. Therefore, targeting the cAMP/PKA/CREB pathway beyond cAMP production makes sense. Redundancy of mechanisms, numerous positive and negative feedback loops, and possibly counteracting effects may limit the effectiveness of targeting downstream pathways. Nevertheless, interventions targeting important regulatory, signaling and pathophysiologic pathways downstream from cAMP/PKA activation may provide additive or synergistic value and build on a strategy that has already had success. The purpose of this manuscript is to review the role of cAMP and PKA signaling and their multiple downstream pathways as potential targets for emergent therapies for ADPKD.

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“…By contrast, hyperactivation of CFTR is central to pathogenesis in secretory diarrhea and autosomal dominant polycystic kidney disease (ADPKD) (3)(4)(5)(6)(7)(8)(9)(10). In both secretory diarrhea and ADPKD, cyclic AMP (cAMP) accumulation activates protein kinase A (PKA) (11)(12)(13)(14)(15). PKAphosphorylation in turn activates CFTR (11,12,(16)(17)(18), leading to excess fluid accumulation in the intestinal lumen and renal cysts, for secretory diarrhea and ADPKD, respectively (19,20).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for CFTR inhibition by CFTR_inh-172

Young,

Levring,

Fiedorczuk

et al. 2023

Preprint

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The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates electrolyte and fluid balance in epithelial tissues. Whereas activation of CFTR is vital to treating cystic fibrosis, selective inhibition of CFTR is a potential therapeutic strategy for secretory diarrhea and autosomal dominant polycystic kidney disease (ADPKD). Although several CFTR inhibitors have been developed by high-throughput screening, their modes of action remain elusive. In this study, we determined the structure of CFTR in complex with the inhibitor CFTRinh-172 to 2.7 Å resolution by cryogenic electron microscopy (cryo-EM). We observe that CFTRinh-172 binds inside the pore near transmembrane helix 8 (TM8), a critical structural element that links ATP hydrolysis with channel gating. Binding of CFTRinh-172 stabilizes a conformation in which the chloride selectivity filter is collapsed and the pore is blocked from the extracellular side of the membrane. Single molecule fluorescence resonance energy transfer (smFRET) experiments indicate that CFTRinh-172 inhibits channel gating without compromising nucleotide-binding domain (NBD) dimerization. Together, these data show that CFTRinh-172 acts as both a pore blocker and a gating modulator, setting it apart from typical ion channel inhibitors. The dual functionality of CFTRinh-172 reconciles previous biophysical observations and provides a molecular basis for its activity.

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Loss of Polycystin-1 causes cAMP-dependent switch from tubule to cyst formation

Cited by 8 publications

References 48 publications

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling

Structural basis for CFTR inhibition by CFTR_inh-172

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Loss of Polycystin-1 causes cAMP-dependent switch from tubule to cyst formation

Cited by 8 publications

References 48 publications

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling

Structural basis for CFTR inhibition by CFTRinh-172

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Structural basis for CFTR inhibition by CFTR_inh-172