Clinical effects of calcium channel blockers and renin-angiotensin-aldosterone system inhibitors on changes in the estimated glomerular filtration rate in patients with polycystic kidney disease

Mitobe, Michihiro; Yoshida, Takemi; Sugiura, Hidekazu; Shiohira, Shunji; Shimada, Katsunori; Nitta, Kosaku; Tsuchiya, Ken

doi:10.1007/s10157-010-0329-5

Cited by 20 publications

(11 citation statements)

References 19 publications

(27 reference statements)

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“…Because hypertension in PKD is still poorly understood, the hypertensive therapy has not been much different than therapy for hypertension in other chronic kidney diseases. L-type calcium channel blockers have been tested in PKD patients to control their blood pressure [14,15]. Considering the fact that calcium level is lower in cystic than normal epithelia [1–4], understanding the roles of L-type calcium channel in PKD is scientifically and clinically imperative.…”

Section: Introductionmentioning

confidence: 99%

L-type calcium channel modulates cystic kidney phenotype

Jin

Muntean

Aal-Aaboda

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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In polycystic kidney disease (PKD), abnormal proliferation and genomic instability of renal epithelia have been associated with cyst formation and kidney enlargement. We recently showed that L-type calcium channel (Cav1.2) is localized to primary cilia of epithelial cells. Previous studies have also shown that low intracellular calcium level was associated with the hyperproliferation phenotype in the epithelial cells. However, the relationship between calcium channel and cystic kidney phenotype is largely unknown. In this study, we generated cells with somatic deficient Pkd1 or Pkd2 to examine ciliary CaV1.2 function via lentiviral knockdown or pharmacological verapamil inhibition. Although inhibition of CaV1.2 expression or function did not change division and growth patterns in wild-type epithelium, it led to hyperproliferation and polyploidy in mutant cells. Lack of CaV1.2 in Pkd mutant cells also decreased the intracellular calcium level. This contributed to a decrease in CaM kinase activity, which played a significant role in regulating Akt and Erk signaling pathways. Consistent with our in vitro results, CaV1.2 knockdown in zebrafish and Pkd1 heterozygous mice facilitated the formation of kidney cysts. Larger cysts were developed faster in Pkd1 heterozygous mice with CaV1.2 knockdown. Overall, our findings emphasized the importance of CaV1.2 expression in kidneys with somatic Pkd mutation. We further suggest that CaV1.2 could serve as a modifier gene to cystic kidney phenotype.

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Section: Introductionmentioning

confidence: 99%

L-type calcium channel modulates cystic kidney phenotype

Jin

Muntean

Aal-Aaboda

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Treatment with this molecule improved renal function in a mouse model for ADPKD, inhibiting cyst expansion by restoring normal calcium signaling and cell proliferation [45,46] . Conversely, retrospective studies have shown that treating ADPKD patients with calcium channel blockers provokes a worsening of renal function, as compared to untreated patients, by reducing the glomerular filtration rate [47] . However, treatment of PKD2(-/WS25) ADPKD mice with R-568, a type-2 calcimimetic molecule that triggers the activation of calcium-sensing receptors, showed no detectable effect on cystogenesis [48] .…”

Section: Calcium Channels As a Target For Adpkd Therapymentioning

confidence: 99%

Role of calcium in polycystic kidney disease: From signaling to pathology

Mangolini

Stephanis

Aguiari

2016

WJN

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 (PC1), a large multi-functional membrane receptor protein able to regulate ion channel complexes, whereas polycystin-2 (PC2), encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum (ER). In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this field could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression.

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“…in Cy/+ rats, decrease of intercellular ca 2+ by treatment with L-type calcium channel blocker (ccB) accelerates PKD progression with increased ErK activity in the cystic cells [33]. after these preclinical findings were reported, a careful clinical study was performed, and the results suggested that ccB should be avoided in aDPKD patients unless ccB treatment for resistant hypertension is necessary [27].…”

Section: Mammalian Target Of Rapamycin (Mtor) Signaling Pathwaymentioning

confidence: 99%

Animal Models for Human Polycystic Kidney Disease

et al. 2012

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Polycystic kidney disease (PKD) is a hereditary disorder with abnormal cellular proliferation, fluid accumulation in numerous cysts, remodeling of extracellular matrix, inflammation, and fibrosis in the kidney and liver. The two major types of PKD show autosomal dominant (ADPKD) or autosomal recessive inheritance (ARPKD). ADPKD is one of the most common genetic diseases, with an incidence of 1:500-1,000. Approximately 50% of patients with ADPKD develop end-stage renal disease (ESRD) by the age of 60. On the other hand, ARPKD is relatively rare, with an incidence of approximately 1:20,000-40,000. ARPKD is diagnosed early in life, often prenatally. The gene products responsible for ADPKD and ARPKD distribute in primary cilia and are thought to control intercellular Ca 2+ . Two types of animal model of PKD have been established: spontaneous hereditary models identified by the typical manifestations of PKD and gene-engineered models established by modification of human orthologous genes. Both types of animal models are used to study the mechanism of cystogenesis and efficacy of medical treatments. In PKD progression, critical roles of signaling pathways including MAPK, mTOR, and PPAR-γ have been discovered with these models. Therefore, experimental animal models are indispensable for investigating molecular mechanisms of PKD onset and progression as well as potential therapeutic treatments.

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Clinical effects of calcium channel blockers and renin-angiotensin-aldosterone system inhibitors on changes in the estimated glomerular filtration rate in patients with polycystic kidney disease

Abstract: These results suggest that from a renoprotective perspective, CCB should possibly be avoided in patients with PKD unless treatment for resistant hypertension is necessary.

Cited by 20 publications

References 19 publications

L-type calcium channel modulates cystic kidney phenotype

L-type calcium channel modulates cystic kidney phenotype

Role of calcium in polycystic kidney disease: From signaling to pathology

Animal Models for Human Polycystic Kidney Disease

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