Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited kidney disorders and is characterized by the progressive formation and expansion of fluid filled cysts, ultimately leading to kidney failure. Although caused by reduced dosage of the polycystin proteins, the disease phenotype arises from a broad disruption of epithelial physiology rather than a single linear pathway. Loss of polycystin function destabilizes epithelial homeostasis and sensitizes cyst lining cells to proliferative and secretory cues. A central consequence is the emergence of a self reinforcing signaling environment in which cyclic AMP, Ca2+, and purinergic pathways amplify one another, promoting chloride driven fluid secretion and epithelial proliferation. In parallel, cyst epithelia exhibit disturbed cell turnover, including altered proliferation, apoptosis, autophagy, and ferroptotic stress, which reshape luminal architecture and sustain a pro secretory microenvironment. Metabolic reprogramming, characterized by enhanced glycolysis, mitochondrial dysfunction, and redox imbalance, provides energetic support for these processes and further strengthens proliferative and secretory signaling. Hypoxia inducible factor 1α (HIF 1α) integrates hypoxic, metabolic, and mechanical cues into transcriptional programs that reinforce cyst expansion. This review synthesizes these interconnected mechanisms and highlights potential therapeutic strategies, including restoration of polycystin expression, modulation of cAMP and purinergic signaling, inhibition of chloride secretion, metabolic targeting, and HIF 1α pathway intervention. Together, these insights support a model in which cyst growth arises from mutually reinforcing signaling, metabolic, and transcriptional programs. Effective disease modification will likely require multi nodal therapeutic approaches that address this integrated network.
R. Ursu, B. Buchholz, K. Skoczynski· American Journal of Physiolo...· 0 citations
Autosomal recessive polycystic kidney disease (ARPKD) is caused by impaired function of fibrocystin/polyductin (FPC) in collecting duct epithelia resulting in cyst formation. We hypothesized that the membrane-bound C-terminal FPC domain (FPCct) is necessary to suppress cystogenesis and facilitate epithelial homeostasis. In ARPKD, cystic kidney epithelia are characterized by a secretory phenotype associated with high intracellular cAMP levels and enhanced STAT3-dependent transcription. Moreover, impaired FPC function may lead to enhanced activation of Src tyrosine kinase, thereby activating STAT3 signaling and its downstream transcriptional activity. To investigate the effects of FPC loss on the cystic epithelial cell phenotype, we used an established principal-like MDCK cell line (pl-MDCK) and studied monolayers in both two and three-dimensional culture. In this in vitro model of collecting duct epithelia, FPC-deficient cells showed two-fold elevated basal cAMP levels and enhanced apical secretion leading to three-fold higher luminal pressure. Forskolin-stimulated elevation of cAMP levels triggered enhanced Src-dependent activation of STAT3 resulting in a pronounced cystic phenotype. Notably, expression of wildtype FPCct reduced both STAT3-dependent transcription and the secretory phenotype in knockout epithelial cells. Our data suggest that FPCct interacts with Src kinase at the plasma membrane, thereby reducing Src-mediated STAT3 phosphorylation and limiting STAT3-dependent transcription. Thus, FPCct appears to act like a physiological suppressor of cystogenic signaling, as found in healthy kidney epithelia, that is essential for maintaining epithelial homeostasis. Protein constructs that restore FPC C-terminal function may offer a therapeutic lead to mitigate epithelial dysfunction and slow disease progression in ARPKD.
F. Hassan, Susanne T. Hahnenstein, A. Kraus et al.· American Journal of Physiolo...· 0 citations