Molecular Pathways and Therapies in Autosomal-Dominant Polycystic Kidney Disease

Saigusa, Takamitsu; Bell, P. Darwin

doi:10.1152/physiol.00032.2014

Cited by 48 publications

(53 citation statements)

References 162 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ADPKD results from loss-of-function mutations in polycystin (PKD) 1 or 2 genes, which disrupt the normal differentiated phenotype of the renal tubular epithelium, leading to increases in intracellular cyclic adenosine 3′,5′-monophosphate (cAMP), and resulting in increased cellular proliferation and cyst formation [2]. Cyst growth displaces and damages normal kidney tissue, leading to a decrease in nephron function.…”

Section: Introductionmentioning

confidence: 99%

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

Wang¹,

Constans²,

Chebib³

et al. 2019

Am J Nephrol

View full text Add to dashboard Cite

Background: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. Methods: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3′,5′-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. Results: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. Conclusions: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

show abstract

Section: Introductionmentioning

confidence: 99%

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

Wang¹,

Constans²,

Chebib³

et al. 2019

Am J Nephrol

View full text Add to dashboard Cite

show abstract

“…ADPKD is recessive at the cellular level and cysts develop clonally from a tubular cell only once the cell has acquired a second somatic mutation to inactivate the remaining normal allele (7). A somatic "second-hit" mutation, loss of heterozygosity, or haploinsufficiency may account for the mosaic nature of cyst formation, while in the mature organ, broad and fast cyst formation requires a third hit such as kidney injury (8)(9)(10). Recent evidences suggest that a complete loss of function is not required for cystogenesis; rather, functional PC1 or PC2 must be reduced to a certain threshold level (1).…”

Section: Introductionmentioning

confidence: 99%

Novel Therapeutic Strategies Targeting Molecular Pathways of Cystogenesis in Autosomal Polycystic Kidney Disease

Salvadori

Tsalouchos

2017

jrenhep

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease that results from mutations in PKD1 or PKD2. The disease is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells that destroy the architecture of the renal parenchyma and lead to kidney failure. Until recently, the causes and the molecular pathways that lead to cystogenesis remained obscure. In the last decade, enormous progress has been made in understanding the pathogenesis of ADPKD and the development of new therapies. The purpose of this review is to update on the promising therapies that are being developed and tested based on knowledge of recent advances in molecular and cellular targets involved in cystogenesis.

show abstract

“…The wisdom of this conclusion is elegantly articulated in the review of novel therapies for autosomal dominant polycystic kidney disease (ADPKD) by Saigusa and Bell in this issue of Physiology (6). ADPKD is an inherited disorder that leads to the formation of multiple renal cysts and ultimately leads to renal failure (6).…”

mentioning

confidence: 99%

“…ADPKD is an inherited disorder that leads to the formation of multiple renal cysts and ultimately leads to renal failure (6). ADPKD results from mutations in either the polycystin 1 or polycystin 2 proteins, which result from the PKD1 or PKD2 genes, respectively (6). These proteins are located in the primary cilium (4,6).…”

mentioning

confidence: 99%

Understanding Renal Physiology Leads to Therapeutic Advances in Renal Disease

Sands

2015

Physiology

View full text Add to dashboard Cite

Molecular Pathways and Therapies in Autosomal-Dominant Polycystic Kidney Disease

Cited by 48 publications

References 162 publications

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

Novel Therapeutic Strategies Targeting Molecular Pathways of Cystogenesis in Autosomal Polycystic Kidney Disease

Understanding Renal Physiology Leads to Therapeutic Advances in Renal Disease

Contact Info

Product

Resources

About