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Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling.

ABSTRACT: Mutations in PKD1 (encoding for polycystin-1 [PC1]) are found in 80%-85% of patients with autosomal dominant polycystic kidney disease (ADPKD). We tested the hypothesis that changes in actin dynamics result from PKD1 mutations through dysregulation of compartmentalized centrosomal RhoA signaling mediated by specific RhoGAP (ARHGAP) proteins resulting in the complex cellular cystic phenotype. Initial studies revealed that the actin cytoskeleton was highly disorganized in cystic cells derived from patients with PKD1 and was associated with an increase in total and centrosomal active RhoA and ROCK signaling. Using cilia length as a phenotypic readout for centrosomal RhoA activity, we identified ARHGAP5, -29, and -35 as essential regulators of ciliation in normal human renal tubular cells. Importantly, a specific decrease in centrosomal ARHGAP35 was observed in PKD1-null cells using a centrosome-targeted proximity ligation assay and by dual immunofluorescence labeling. Finally, the ROCK inhibitor hydroxyfasudil reduced cyst expansion in both human PKD1 3D cyst assays and an inducible Pkd1 mouse model. In summary, we report a potentially novel interaction between PC1 and ARHGAP35 in the regulation of centrosomal RhoA activation and ROCK signaling. Targeting the RhoA/ROCK pathway inhibited cyst formation in vitro and in vivo, indicating its relevance to ADPKD pathogenesis and for developing new therapies to inhibit cyst initiation.

SUBMITTER: Streets AJ

PROVIDER: S-EPMC7455122 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling.

Streets Andrew J AJ Prosseda Philipp P PP Ong Albert Cm AC

JCI insight 20200820 16

Mutations in PKD1 (encoding for polycystin-1 [PC1]) are found in 80%-85% of patients with autosomal dominant polycystic kidney disease (ADPKD). We tested the hypothesis that changes in actin dynamics result from PKD1 mutations through dysregulation of compartmentalized centrosomal RhoA signaling mediated by specific RhoGAP (ARHGAP) proteins resulting in the complex cellular cystic phenotype. Initial studies revealed that the actin cytoskeleton was highly disorganized in cystic cells derived from ...[more]

PMID: 32663194

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Project description:Abstract Background Melatonin (MEL), an endogenous hormone, has been widely investigated in neurological diseases. Microglia (MG), a resident immunocyte localizing in central nervous system is reported to play important functions in the animal model of temporal lobe epilepsy (TLE). Some evidence showed that MEL influenced activation of MG, but the detailed model of action that MEL plays in remains uncertain. Methods In this study, we established a model of TLE in mice by stereotactic injection of kainic acid (KA). We treated the mice with MEL. Lipopolysaccharide, ROCK2‐knockdown (ROCK‐KD) and ‐overexpression (ROCK‐OE) of lentivirus‐treated cells were used in cell experiments to simulate an in vitro inflammatory model. Results The results of electrophysiological tests showed that MEL reduced frequency and severity of seizure. The results of behavioral tests indicated MEL improved cognition, learning, and memory ability. Histological evidences demonstrated a significant reduction of neuronal death in the hippocampus. In vivo study showed that MEL changed the polarization status of MG from a proinflammatory M1 phenotype to an anti‐inflammatory M2 phenotype by inversely regulating the RhoA/ROCK signaling pathway. In cytological study, we found that MEL had a significant protective effect in LPS‐treated BV‐2 cells and ROCK‐KD cells, while the protective effect of MEL was significantly attenuated in ROCK‐OE cells. Conclusion MEL played an antiepileptic role in the KA‐induced TLE modeling mice both in behavioral and histological levels, and changed MG polarization status by regulating the RhoA/ROCK signaling pathway. 1. Melatonin (MEL) reduces frequency and severity of seizure. 2. MEL regulates the ROCK2 signaling pathway rather than ROCK1 to promote microglial polarization toward an anti‐inflammatory direction. 3. RhoA/ROCK2 signaling pathway might be a potential mechanism in the status epilepticus modeling mice. Highlights • Melatonin (MEL) reduces frequency and severity of seizure.• MEL regulates the ROCK2 signaling pathway rather than ROCK1 to promote microglial polarization toward an anti‐inflammatory direction.• RhoA/ROCK2 signaling pathway may be important in the temporal lobe epilepsy modeling mice.

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Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling.

Publications

Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling.

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