piperidines and Polycystic-Kidney--Autosomal-Dominant

Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal genetic disorder, however it still lacks a cure. The discovery of new therapies heavily depends on understanding key signalling pathways that lead to ADPKD. The JAnus Kinase and Signal Transducers and Activators of Transcription (JAK/STAT) pathway is aberrantly activated and contributes to ADPKD pathogenesis via enhancing epithelial proliferation. Yet the mechanisms underlying the upregulation of JAK/STAT activity in this disease context is completely unknown. Here, we investigate the role of JAK2 in ADPKD using a murine model of ADPKD (Pkd1

Topics: Animals; Cell Line; Cell Proliferation; Curcumin; Disease Models, Animal; Epithelial Cells; Humans; Janus Kinase 2; Kidney; Mice; Phosphorylation; Piperidines; Polycystic Kidney, Autosomal Dominant; Pyrimidines; Pyrroles; TRPP Cation Channels; Up-Regulation

Positive transcription elongation factor b (P-TEFb) functions as a central regulator of transcription elongation. Activation of P-TEFb occurs through its dissociation from the transcriptionally inactive P-TEFb/HEXIM1/7SK snRNP complex. However, the mechanisms of signal-regulated P-TEFb activation and its roles in human diseases remain largely unknown. Here, we demonstrate that cAMP-PKA signaling disrupts the inactive P-TEFb/HEXIM1/7SK snRNP complex by PKA-mediated phosphorylation of HEXIM1 at serine-158. The cAMP pathway plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD), and we show that P-TEFb is hyperactivated in mouse and human ADPKD kidneys. Genetic activation of P-TEFb promotes cyst formation in a zebrafish ADPKD model, while pharmacological inhibition of P-TEFb attenuates cyst development by suppressing the pathological gene expression program in ADPKD mice. Our study therefore elucidates a mechanism by which P-TEFb activation by cAMP-PKA signaling promotes cystogenesis in ADPKD.

Topics: Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cysts; Disease Models, Animal; Flavonoids; Humans; Kidney; Mice; Mice, Knockout; Phosphorylation; Piperidines; Polycystic Kidney, Autosomal Dominant; Positive Transcriptional Elongation Factor B; Protein Binding; Ribonucleoproteins, Small Nuclear; RNA-Binding Proteins; Signal Transduction; Transcription Factors; TRPP Cation Channels; Zebrafish