Biology subjects

Aka, A.

Publications and source records attributed to Aka, A..

3 recordsLinked to original sources

bioRxiv2026

A cilia-dependent inflammatory programme links bacterial detection to kidney disease

The primary cilium is a microtubule-based sensory organelle projecting from the plasma membrane of most mammalian cells. Genetic defects in ciliary components cause chronic kidney disease (CKD) characterized by heightened production of inflammatory and fibrogenic mediators by tubular epithelial cells. Yet, whether this reflects a physiological role of the primary cilium remains unknown. Here, we show that primary cilia on kidney tubular cells bind uropathogenic Escherichia coli and, in response to bacterial components, initiate a fibro-inflammatory program reminiscent of CKD. Integrating single-cell transcriptomics with conditional mouse models, we observed that epithelial cilia orchestrate a similar fibro-inflammatory response in the absence of infection during CKD. This convergence reveals a shared cilia-dependent signalling axis governing both host-pathogen responses and CKD progression. Mechanistically, cilia ablation selectively impairs tubular responses to ADP-heptose, a pathogen-associated molecular pattern that activates NF-{kappa}B via the cytosolic innate immune receptor ALPK1. In human kidney organoids, ADP-heptose induces robust fibro-inflammation, and genetic or pharmacological inhibition of ALPK1 attenuates this response in a rodent CKD model. Together, these findings identify primary cilia as central orchestrators of a fibro-inflammatory program linking pathogen detection to kidney disease progression.

physiology↗

bioRxiv2024

Cilia to basement membrane signalling is a biomechanical driver of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD), which affects around 4 million patients worldwide, is characterized by the formation of multiple tubule derived cysts, which grossly enlarge both kidneys and progressively compromise renal function. ADPKD mainly results from mutations in PKD1, leading to the loss of polycystin-1 protein, which localizes to primary cilia. Primary cilia are required for cyst formation but the biomechanical changes underlying cystogenesis upon loss of polycytin-1 are unknown. We find that cilia and polycystin-1 shape the tubular basement membrane (TBM). Combining orthologous mouse models with a tubule-on-chip approach allowing manipulations of TBM stiffness, we find that cilia regulate the composition and biomechanical properties of the TBM. In the setting of polycytin-1 loss, reduced TBM stiffness and increased luminal pressure act as biomechanical drivers of cyst formation. These findings suggest a novel biomechanical model for ADPKD and unveil that cilia to TBM signalling controls kidney shape.

physiology↗

bioRxiv2019

Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

The inactivation of the ciliary proteins polycystin 1 or 2 leads to autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of chronic kidney disease. Both cilia signaling and interstitial inflammation play a critical role in the disease. Yet, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, which is suspected to fuel ADPKD progression, is involved in crosstalks between immune and non-immune cells in various tissues and is a component of the cilia proteome. Here, we explore how STAT3 intersects with cilia signaling, renal inflammation and cyst growth using conditional murine models of post-developmental Pkd1, Stat3 and cilia ablation. Our results indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes STAT3 activation. Surprisingly, while disrupting Stat3 in Pkd1 deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. Mechanistically, STAT3 represses the expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. These results demonstrate that STAT3 is not a critical driver of cyst growth in ADPKD but plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

pathology↗