Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)

Ilatovskaya, Daria V.; Levchenko, Vladislav; Pavlov, Tengis S.; Isaeva, Elena; Klemens, Christine A.; Johnson, J. R.; Liu, Pengyuan; Kriegel, Alison J.; Staruschenko, Alexander

doi:10.1016/j.ebiom.2019.01.006

Cited by 26 publications

(24 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The pathogenic effect of the excessive ATP level in PKDs has been summarized in reviews by Rangan (28) and Ilatovskaya et al (12). In particular, a remodeled P2 receptor profile (a shift from metabotropic P2Y to ionotropic P2X signaling) can cause improper intracellular calcium handling, increased chloride secretion, and impaired sodium reabsorption in the cystic epithelial cells and enhanced proliferation of cystic epithelia (9,13,24,27,30).…”

Section: Introductionmentioning

confidence: 99%

Knockout ofP2rx7purinergic receptor attenuates cyst growth in a rat model of ARPKD

Arkhipov

Potter

Geurts

et al. 2019

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

The severity of polycystic kidney diseases (PKD) depends on the counterbalancing of genetic predisposition and environmental factors exerting permissive or protective influence on cyst development. One poorly characterized phenomenon in the cystic epithelium is abnormal purinergic signaling. Earlier experimental studies revealed the high importance of the ionotropic P2X receptors (particularly, P2X7) in the pathophysiology of the cyst wall. To study mechanisms of P2X7 involvement in cyst growth and aspects of targeting these receptors in PKD treatment we performed a CRISPR/SpCas9-mediated global knockout of the P2rx7 gene in PCK rats, a model of autosomal recessive PKD (ARPKD). A single base insertion in exon 2 of the P2rx7 gene in the renal tissues of homozygous mutant animals leads to lack of P2X7 protein that did not affect their viability or renal excretory function. However, PCK. P2rx7 rats demonstrated slower cyst growth (but not formation of new cysts) compared with heterozygous and PCK. P2rx7+ littermates. P2X7 receptors are known to activate pannexin-1, a plasma channel capable of releasing ATP, and we found here that pannexin-1 expression in the cystic epithelium is significantly higher than in nondilated tubules. P2X7 deficiency reduces renal pannexin-1 protein expression and daily urinary ATP excretion. Patch-clamp analysis revealed that lack of P2X7 increases epithelial sodium channel activity in renal tissues and restores impaired channel activity in cysts. Interpretation of our current data in the context of earlier studies strongly suggests that P2X7 contributes to cyst growth by increasing pannexin-1-dependent pathogenic ATP release into the lumen and reduction of sodium reabsorption across the cyst walls.

show abstract

Section: Introductionmentioning

confidence: 99%

Knockout ofP2rx7purinergic receptor attenuates cyst growth in a rat model of ARPKD

Arkhipov

Potter

Geurts

et al. 2019

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In seeming contradiction, Veizis et al (20) have reported that ENaC-mediated Na ϩ absorption is decreased in the collecting ducts of ARPKD BPK mice and that a reduction in Na ϩ absorption contributes to the accumulation of cyst fluid. Ilatovskaya et al (21) may have resolved this apparent contradiction by showing that ENaC function is severely decreased in the PCK/CrljCrlPkhd1pck/CRL (PCK) rat model of ARPKD, when the rats are placed on a salt-restricted diet. Because the cysts get worse when the rats are on a restricted diet, it is clear that ablation of ENaC activity allows the cysts to accumulate fluid.…”

mentioning

confidence: 99%

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease

Yanda

Cha

Cebotaru

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Phyllis I. Hanson Autosomal-dominant polycystic kidney disease (ADPKD) induces a secretory phenotype, resulting in multiple fluid-filled cysts. We have previously demonstrated that VX-809, a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR), reduces cyst growth. Here, we show that in normal mice CFTR is located within the cells and also at the apical and basolateral membranes. However, in polycystic kidney disease (pkd1)-knockout mice, CFTR was located at the plasma membrane, consistent with its role in cAMP-dependent fluid secretion. In cystic mice, VX-809 treatment increased CFTR levels at the apical membrane and reduced its association with the endoplasmic reticulum. Surprisingly, VX-809 treatment significantly increased CFTR's co-localization with the basolateral membrane in cystic mice. Na ؉ /H ؉ exchanger 3 (NHE3) is present in pkd1-knockout and normal mice and in proximal tubule-derived, cultured pkd1-knockout cells. VX-809 increased the expression, activity, and apical plasma membrane localization of NHE3. Co-localization of epithelial sodium channel (ENaC) with the plasma membrane was reduced in cysts in pkd1-knockout mice, consistent with an inability of the cysts to absorb fluid. Interestingly, in the cystic mice, VX-809 treatment increased ENaC levels at the apical plasma membrane consistent with fluid absorption. Thus, VX-809 treatment of pkd1-null mouse kidneys significantly affected CFTR, NHE3, and ENaC, altering the cyst phenotype from one poised toward fluid secretion toward one more favorable for absorption. VX-809 also altered the location of CFTR but not of NHE3 or ENaC in normal mice. Given that VX-809 administration is safe, it may have potential utility for treating patients with ADPKD.

show abstract

“…First, the expression of PKHD1 is post-transcriptionally negatively regulated by miR-365-1 [ 86 ]. Second, the downregulation of epithelial sodium channel (ENaC) mediated by miR-9a-5p, which was upregulated in collecting duct cells, contributed to delay cyst growth in salt deficient diet fed PCK rat, an ARPKD model [ 47 ].…”

Section: Noncoding Rna In Polycystic Kidney Diseasementioning

confidence: 99%

Non-Coding RNAs in Hereditary Kidney Disorders

Zhou

2021

IJMS

View full text Add to dashboard Cite

Single-gene defects have been revealed to be the etiologies of many kidney diseases with the recent advances in molecular genetics. Autosomal dominant polycystic kidney disease (ADPKD), as one of the most common inherited kidney diseases, is caused by mutations of PKD1 or PKD2 gene. Due to the complexity of pathophysiology of cyst formation and progression, limited therapeutic options are available. The roles of noncoding RNAs in development and disease have gained widespread attention in recent years. In particular, microRNAs in promoting PKD progression have been highlighted. The dysregulated microRNAs modulate cyst growth through suppressing the expression of PKD genes and regulating cystic renal epithelial cell proliferation, mitochondrial metabolism, apoptosis and autophagy. The antagonists of microRNAs have emerged as potential therapeutic drugs for the treatment of ADPKD. In addition, studies have also focused on microRNAs as potential biomarkers for ADPKD and other common hereditary kidney diseases, including HNF1β-associated kidney disease, Alport syndrome, congenital abnormalities of the kidney and urinary tract (CAKUT), von Hippel–Lindau (VHL) disease, and Fabry disease. This review assembles the current understanding of the non-coding RNAs, including microRNAs and long noncoding RNAs, in polycystic kidney disease and these common monogenic kidney diseases.

show abstract

Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)

Cited by 26 publications

References 88 publications

Knockout ofP2rx7purinergic receptor attenuates cyst growth in a rat model of ARPKD

Knockout ofP2rx7purinergic receptor attenuates cyst growth in a rat model of ARPKD

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease

Non-Coding RNAs in Hereditary Kidney Disorders

Contact Info

Product

Resources

About