Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases

Vasileva, Valeria; Sultanova, Regina; Sudarikova, Anastasia V.; Ilatovskaya, Daria V.

doi:10.3389/fphys.2021.693130

Cited by 20 publications

(26 citation statements)

References 179 publications

(240 reference statements)

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“…Therefore, the role of ciliary mechanosensation in the regulation of Ca 2+ handling is still being debated. For more detailed information on the ciliary signaling disruptions that lead to PKD, please refer to a recent review by our group that highlighted this topic [ 114 ].…”

Section: Regulation Of Calcium Handling In Pkd: Polycystins Cilia Calcium Channels Transporters and Purinergic Signaling-dependent Calciumentioning

confidence: 99%

Recent advances in understanding ion transport mechanisms in polycystic kidney disease

et al. 2021

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This review focuses on the most recent advances in the understanding of the electrolyte transport-related mechanisms important for the development of severe inherited renal disorders, autosomal dominant (AD) and recessive (AR) forms of polycystic kidney disease (PKD). We provide here a basic overview of the origins and clinical aspects of ARPKD and ADPKD and discuss the implications of electrolyte transport in cystogenesis. Special attention is devoted to intracellular calcium handling by the cystic cells, with a focus on polycystins and fibrocystin, as well as other calcium level regulators, such as transient receptor potential vanilloid type 4 (TRPV4) channels, ciliary machinery, and purinergic receptor remodeling. Sodium transport is reviewed with a focus on the epithelial sodium channel (ENaC), and the role of chloride-dependent fluid secretion in cystic fluid accumulation is discussed. In addition, we highlight the emerging promising concepts in the field, such as potassium transport, and suggest some new avenues for research related to electrolyte handling.

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Section: Regulation Of Calcium Handling In Pkd: Polycystins Cilia Calcium Channels Transporters and Purinergic Signaling-dependent Calciumentioning

confidence: 99%

Recent advances in understanding ion transport mechanisms in polycystic kidney disease

et al. 2021

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“…PKD1 mutations are responsible for 80% of ADPKD cases, while around 15% of cases are attributed to PKD2 mutations. The remaining cases are due to rare or unknown genetic abnormalities in other loci ( Vasileva et al, 2021 ). ARPKD is less common than ADPKD with a reported incidence of 1 in 26,500 live births ( Bergmann et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Non-coding RNAs as potential biomarkers and therapeutic targets in polycystic kidney disease

Zheng

Reid²,

Eccles³

et al. 2022

Front. Physiol.

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Polycystic kidney disease (PKD) is a significant cause of end-stage kidney failure and there are few effective drugs for treating this inherited condition. Numerous aberrantly expressed non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), may contribute to PKD pathogenesis by participating in multiple intracellular and intercellular functions through post-transcriptional regulation of protein-encoding genes. Insights into the mechanisms of miRNAs and other ncRNAs in the development of PKD may provide novel therapeutic strategies. In this review, we discuss the current knowledge about the roles of dysregulated miRNAs and other ncRNAs in PKD. These roles involve multiple aspects of cellular function including mitochondrial metabolism, proliferation, cell death, fibrosis and cell-to-cell communication. We also summarize the potential application of miRNAs as biomarkers or therapeutic targets in PKD, and briefly describe strategies to overcome the challenges of delivering RNA to the kidney, providing a better understanding of the fundamental advances in utilizing miRNAs and other non-coding RNAs to treat PKD.

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“…Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder characterised by the formation of fluid‐filled cysts in the kidneys (Vasileva et al., 2021). ADPKD causes the formation and enlargement of cysts in the kidney and other organs leading to end‐stage renal disease (ESRD) (Nobakht et al., 2020).…”

Section: Introductionmentioning

confidence: 99%

“…ADPKD causes the formation and enlargement of cysts in the kidney and other organs leading to end‐stage renal disease (ESRD) (Nobakht et al., 2020). This pathology is mainly associated with mutations of PKD1 or PKD2 genes encoding for polycystin‐1 and ‐2 (PC1 and PC2), respectively (Vasileva et al., 2021). PC1 and PC2 interacting by each other form the polycystic complex that is localised in the primary cilium of kidney epithelial cells and regulate calcium influx in response to mechanical stimuli (Nobakht et al., 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The main treatment for ADPKD patients remains the dialysis; however, recent findings have allowed a better understanding of the molecular mechanisms linked to cyst formation leading to the discovery of new therapeutic drugs based on the molecular targeting. In particular, the treatment with Tolvaptan, a selective vasopressin receptor 2 (V2R) antagonist, is actually able to slow ADPKD progression (Vasileva et al., 2021). Tolvaptan is first drug approved for ADPKD treatment; nevertheless, ADPKD patients treated with Tolvaptan developed several side effects including thirst, polyuria and liver injury (Riella et al., 2014; Vasileva et al., 2021).…”

Section: Introductionmentioning

confidence: 99%

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The inhibition of MDM2 slows cell proliferation and activates apoptosis in ADPKD cell lines

Patergnani

Giattino

Bianchi

et al. 2022

Biology of the Cell

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Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is characterised by progressive cysts formation and renal enlargement that in most of cases leads to end stage of renal disease (ESRD). This pathology is caused by mutations of either PKD1 or PKD2 genes that encode for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. These proteins function as receptor-channel complex able to regulate calcium homeostasis. PKD1/2 loss of function impairs different signalling pathways including cAMP and mTOR that are considered therapeutic targets for this disease. In fact, Tolvaptan, a vasopressin-2 antagonist that reduces cAMP levels, is the only drug approved for ADPKD treatment. Nevertheless, some ADPKD patients developed side effects in response to Tolvaptan including liver damage. Conversely, mTOR inhibitors that induced disease regression in ADPKD animal models failed the clinical trials. Results: Here, we show that the inhibition of mTOR causes the activation of autophagy in ADPKD cells that could reduce therapy effectiveness by drug degradation through the autophagic vesicles. Consistently, the combined treatment with rapamycin and chloroquine, an autophagy inhibitor, potentiates the decrease of cell proliferation induced by rapamycin. To overcome the dangerous activation of autophagy by mTOR inhibition, we targeted MDM2 (a downstream effector of mTOR signalling) that is involved in TP53 degradation by using RG7112, a small-molecule MDM2 inhibitor used for the treatment of haematologic malignancies. The inhibition of MDM2 by RG7112 prevents TP53 degradation and increases p21 expression leading to the decrease of cell proliferation and the activation of apoptosis. Conclusion:The targeting of MDM2 by RG7112 might represent a new therapeutic option for the treatment of ADPKD.

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Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases

Cited by 20 publications

References 179 publications

Recent advances in understanding ion transport mechanisms in polycystic kidney disease

Recent advances in understanding ion transport mechanisms in polycystic kidney disease

Non-coding RNAs as potential biomarkers and therapeutic targets in polycystic kidney disease

The inhibition of MDM2 slows cell proliferation and activates apoptosis in ADPKD cell lines

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