Jul 2026· American Journal of Physiology - Cell Physiology· 0 citations
Medicine
TL;DR
A model in which cyst growth arises from mutually reinforcing signaling, metabolic, and transcriptional programs is synthesized, which support a model in which cyst growth arises from mutually reinforcing signaling, metabolic, and transcriptional programs.
Abstract
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.
Autosomal dominant polycystic kidney disease (ADPKD), the most prevalent hereditary kidney disorder, is characterized by the progressive formation and expansion of kidney cysts that ultimately destroy normal renal parenchyma. Runt‐related transcription factor 1 (Runx1), a highly conserved regulator of gene expression, orchestrates diverse cellular signaling pathways. Here, we identify Runx1 as a critical driver of cyst growth in ADPKD. Runx1 expression is markedly upregulated in Pkd1 mutant renal epithelial cells and kidney tissues through a cAMP‐dependent mechanism. Pharmacological inhibition of Runx1 with its selective inhibitor, Ro5‐3335, significantly attenuates cyst progression in both rapidly and slowly progressive Pkd1 mouse models. Mechanistically, Runx1 enhances proliferation of cyst‐lining epithelial cells by activating the AKT–mTOR, MAPK, and STAT3 signaling cascades, while suppressing p53‐mediated apoptosis. Moreover, Runx1 promotes macrophage infiltration and inflammatory responses via NF‐κB activation and aggravates interstitial fibrosis through the TGF‐β/Smad2 pathway. Collectively, these findings uncover Runx1 as a pivotal regulator of cystic disease progression and highlight it as a promising therapeutic target for ADPKD.
Yue-yue Zhang, Chang Liu, Jun-Chi Liu et al.· The FASEB Journal· 0 citations
Abstract Renal ciliopathies encompass a spectrum of genetic disorders arising from structural or functional impairments of primary cilia, specialized organelles critical for mechanosensation and signal transduction within renal epithelial cells. These disorders are characterized by cystogenesis, driven by dysregulated ciliary signaling, leading to uncontrolled epithelial proliferation, aberrant growth, and loss of cellular polarity. The clinical trajectory evolves from initial cyst formation to advanced tubulointerstitial fibrosis and progressive renal failure. This progression is governed by pathogenic variants in genes encoding ciliary proteins. While advancements in genetic testing have established prenatal diagnosis as a pivotal tool for early identification, definitive diagnosis and therapeutic intervention remain challenging. These difficulties stem from several factors: incomplete understanding of the molecular mechanisms underlying cyst formation and fibrosis; limitations in prenatal diagnostic accuracy owing to phenotypic overlap and incomplete penetrance; and the marked genetic heterogeneity and diverse clinical trajectories of renal ciliopathies. Existing studies have primarily focused on unidirectional modulation of individual pathways, whereas the systematic integration of signaling network cascades remains largely unaddressed. This review systematically elucidates the molecular mechanisms and aberrant signaling pathways in renal ciliopathies, links genetic heterogeneity to clinical phenotypes, and lays a theoretical basis for prenatal diagnosis and novel therapies.
Qiaowei Zhang, S. Xue, Zhi Gao et al.· Journal of cell communicatio...· 0 citations
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst expansion, fibrosis and inflammation, leading to kidney failure. Myofibroblasts (MFs) often accumulate around cysts and promote fibrosis and cyst growth, but the cellular mechanisms enabling their pro-cystogenic activity remain unclear. Here we examined the role of autophagy within MFs, on their paracrine stimulation of cyst expansion in ADPKD.
METHODS
Autophagy was assessed in human ADPKD nephrectomy tissue, primary human ADPKD renal myofibroblasts (ADPKD-MFs) and male RC/RC mouse model of ADPKD using immunostaining, LC3/p62 analyses, and transmission electron microscopy. Autophagy in MFs was inhibited pharmacologically in ADPKD-MFs, or by conditional Atg5 deletion in PDGFRβ-expressing renal stromal cells in RC/RC (RC/RC; Atg5KO) and wild type (WT; Atg5KO) mice.
RESULTS
In human and mouse ADPKD kidneys, we detected LC3 puncta and autophagic organelles within αSMA- expressing MFs. Inhibition of autophagy in ADPKD-MFs blocked their paracrine stimulation of cyst epithelial cell proliferation in vitro. RC/RC; Atg5KO mice showed significantly reduced cystic growth, fibrosis, MF abundance, and improved kidney function. WT; Atg5KO mice showed no abnormalities in kidney structure or function. Targeted metabolomics performed on ADPKD cyst epithelial-cell conditioned media (ADPKD-ECs CM) revealed moderate increase in lactate levels compared to normal human kidney epithelial-cell conditioned media. Furthermore, lactate treatment stabilized hypoxia-inducible factor-1α (HIF1α) in myofibroblasts, while pharmacological inhibition of HIF1α reduced the expression of autophagy-related genes and impaired autophagic flux.
CONCLUSION
These findings reveal that autophagy in MFs is a previously unrecognized driver of cyst expansion and fibrosis in ADPKD. Lactate-mediated HIF1α stabilization in MFs promotes autophagy that is required for their paracrine stimulation of cyst epithelial growth. Targeting MF-specific autophagy or its upstream regulators may represent a therapeutic strategy to limit cyst growth and fibrosis in ADPKD.
Abeda Jamadar, Viji Remadevi, Meekha M. Varghese et al.· Cell communication and signa...· 0 citations
Background Hirschsprung disease (HSCR) is characterized by distal aganglionosis. Persistent postoperative dysmotility and enterocolitis suggest that intrinsic epithelial vulnerabilities may remain within the ganglionic bowel. We here aimed to define both the state of the epithelium and its metabolism in HSCR. Methods Distal colonic tissues from patients with HSCR and non-HSCR controls (HSCR allied disorders) were examined by single-cell RNA sequencing. Particular attention was given to nicotinamide adenine dinucleotide (NAD+) metabolism and oxidative phosphorylation across epithelial subsets. Immunofluorescence and immunohistochemistry for γH2A.X, PARP1, TOM20, KRT20, and poly(ADP-ribose) (PAR) validated transcriptional signatures of cellular stress, metabolic remodeling, and impaired epithelial maturation. Results Compared with control, HSCR epithelium showed marked transcriptional remodeling, with accumulation of stem and transit-amplifying cells, and depletion of differentiated epithelial lineages, indicating impaired epithelial maturation. These changes were most pronounced in the distal ganglionic colon with a reduced epithelial KRT20 signal, where oxidative phosphorylation, ATP synthesis, and lipid and steroid metabolic pathways were broadly suppressed. Key NAD+ biosynthetic enzymes were downregulated, while NAD+-consuming sirtuins and PAR polymerases (PARP) were upregulated, particularly in HSCR ganglionic colon crypt populations. Similarly, HSCR tissues exhibited increased crypt γH2A.X and nuclear PARP1, as well as elevated TOM20 and poly/mono-ADP-ribose staining, consistent with metabolic and genomic stress. Conclusion HSCR epithelium displays metabolic fragility characterized by NAD+ biosynthetic insufficiency, increased NAD+ consumption, mitochondrial remodeling, DNA damage, and impaired epithelial maturation. These epithelial alterations complement enteric nervous system (ENS)-centered disease models and suggest that NAD+-related pathways may represent modifiable programs relevant to postoperative mucosal resilience and susceptibility to Hirschsprung disease-associated enterocolitis (HAEC).
Yitong Zhao, Jielin Yang, Bo Li et al.· World Journal of Pediatric S...· 0 citations
Underused Drosophila melanogaster offers high genomic and pathway conservation, a wealth of genetic tools, and rapid generation times, making it a reliable and sustainable model for mechanistic, genome-wide, and precision medicine studies.
Jay Deloriea, Cody Casey, Lexee Shearer et al.· Journal of Developmental Bio...· 0 citations
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease and is characterized by the formation and growth of fluid-filled renal cysts. With the current treatment tolvaptan not suited for the majority of patients, an urgent need remains for novel therapeutics. We have shown before that activation of adenosine monophosphate activated protein kinase (AMPK) with salsalate ameliorates disease progression in vivo to a similar extent as tolvaptan. Salsalate achieves this by affecting multiple disease mechanisms known to be involved in ADPKD pathogenesis, such as metabolic reprogramming, cell proliferation and inflammation. However, it is unclear to which extent these effects are dependent on AMPK activation or result from secondary target activation. Therefore, we investigated whether salsalate's active compound, salicylate, modulates these processes in Pkd1-/- renal epithelial cell lines, and whether salicylate effects are regulated by AMPK. Our findings indicate that for a large part, the effects of salicylate on targets related to cellular metabolism, cell proliferation and inflammation are dependent on its activation of AMPK. However, we also observed that salicylate induces mitochondrial uncoupling and inhibition of heme synthesis, while other AMPK activators do not, revealing AMPK-independent effects of salicylate in cystic disease. These results provide us with further insights into the working mechanisms of salsalate/salicylate and offer a solid basis for the future development of salsalate as a potential therapeutic for ADPKD.
Anish A. Kanhai, K. Lodder, L. Wisse et al.· Biochimica et biophysica act...· 0 citations