Gender and the effect of gonadal hormones on the progression of inherited polycystic kidney disease in rats

Cowley, Benjamin D.; Rupp, J C; Muessel, Michelle J.; Gattone, Vincent H.

doi:10.1016/s0272-6386(97)90039-1

Cited by 74 publications

(62 citation statements)

References 27 publications

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“…Therefore, under physiologic conditions, endogenous ouabain can readily activate the MEK-ERK pathway in the cyst cells of ADPKD kidneys, representing a factor that may have a direct impact on the growth of the cysts. A variety of circulating factors, hormones, and autocoids have been shown to stimulate the proliferation of renal cyst epithelial cells (21,27,(23)(24)(25)48,49). This study is the first to demonstrate that ouabain, an endogenous steroid hormone, has a positive effect on proliferation of ADPKD cells.…”

Section: Discussionmentioning

confidence: 61%

Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

Nguyen¹,

Wallace²,

Blanco³

2007

Journal of the American Society of Nephrology

108

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In autosomal dominant polycystic kidney disease (ADPKD), cyst formation and enlargement require proliferation of mural renal epithelial cells and the transepithelial secretion of fluid into the cyst cavity. Na,K-ATPase is essential for solute and water transport in ADPKD cells, and ouabain blocks fluid secretion in these cells. By binding to the Na,K-ATPase, ouabain also induces proliferation in some cell types. Surprisingly, it was found that nanomolar concentrations of ouabain, similar to those circulating in blood, induced ADPKD cell proliferation but had no statistically significant effect on normal human kidney (NHK) cells. Ouabain, acting from the basolateral side of the cells, also caused an increase in the level of phosphorylated extracellular signal-regulated kinases (ERK). Mitogen-activated protein kinase kinase (MEK) inhibitor U0126 blocked ouabain-induced ERK activation and cell proliferation, suggesting that ouabain effect is mediated through the MEK-ERK pathway. In contrast to NHK cells, the dose-response curve for ouabain inhibition of Na,K-ATPase activity indicated that approximately 20% of the enzyme in ADPKD cells exhibits a higher affinity for ouabain. The increased ouabain affinity of ADPKD cells was not due to differences in Na,K-ATPase isoform expression because these cells, like NHK cells, possess only the ␣1 and ␤1 subunits. The ␥ variants of the Na,K-ATPase also are expressed in the cells but are elevated in ADPKD cells. Currently, the basis for the differences in ouabain sensitivity of NHK and ADPKD cells is unknown. It is concluded that ouabain stimulates proliferation in ADPKD cells by binding to the Na,K-ATPase with high affinity and via activation of the MEK-ERK pathway.

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Section: Discussionmentioning

confidence: 61%

Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

Nguyen¹,

Wallace²,

Blanco³

2007

Journal of the American Society of Nephrology

108

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“…We determined the amount of cystic change from random fields using point count stereology methods 15 as described previously. 16 The animals utilized for the present study represent a subset of animals in a separate publication in which the effect of R-568 on extraskeletal calcification and bone were examined. 17 We performed immunohistochemistry on paraffin sections of kidney using a primary antibody to the CaR and a secondary antibody with a peroxidase chromagen product.…”

Section: Concise Methodsmentioning

confidence: 99%

Calcimimetic Inhibits Late-Stage Cyst Growth in ADPKD

Gattone

Chen

Sinders

et al. 2009

Journal of the American Society of Nephrology

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In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/ϩ) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P Ͻ 0.001) and by 19% in the Ca group (P Ͻ 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.

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“…Hematoxylin-eosin-stained sections were used to determine the cyst volume density (CVD). This was performed by a reviewer, blinded to the identity of the treatment modality, using point-counting stereology (6). Areas of the cortex at 90°, 180°, and 270°from the hilum of each section were selected to guard against field selection variation.…”

Section: Animalsmentioning

confidence: 99%

mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease

Belibi¹,

Ravichandran²,

Zafar³

et al. 2011

American Journal of Physiology-Renal Physiology

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Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser473) Akt (p-Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser657) PKCα, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser473) was decreased by rapamcyin. PKCα (Ser657) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser473) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats.

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Gender and the effect of gonadal hormones on the progression of inherited polycystic kidney disease in rats

Cited by 74 publications

References 27 publications

Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

Calcimimetic Inhibits Late-Stage Cyst Growth in ADPKD

mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease

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