scholarly journals 2-Hydroxyestradiol slows progression of experimental polycystic kidney disease

2012 ◽  
Vol 302 (5) ◽  
pp. F636-F645 ◽  
Author(s):  
Sharon Anderson ◽  
Terry T. Oyama ◽  
Jessie N. Lindsley ◽  
William E. Schutzer ◽  
Douglas R. Beard ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Renal Plasma Flow ◽  
Mammalian Target Of Rapamycin ◽  
Polycystic Kidney ◽  
Downstream Effectors ◽  
Cortex Area ◽  
Slow Progression ◽  
17Β Estradiol ◽  
Estradiol Metabolites

Male gender is a risk factor for progression of polycystic kidney disease (PKD). 17β-Estradiol (E2) protects experimentally, but clinical use is limited by adverse effects. Novel E2 metabolites provide many benefits of E2 without stimulating the estrogen receptor, and thus may be safer. We hypothesized that E2 metabolites are protective in a model of PKD. Studies were performed in male control Han:SPRD rats, and in cystic males treated with orchiectomy, 2-methoxyestradiol, 2-hydroxyestradiol (2-OHE), or vehicle, from age 3 to 12 wk. Cystic rats exhibited renal functional impairment (∼50% decrease in glomerular filtration and renal plasma flow rates, P < 0.05) and substantial cyst development (20.5 ± 2.0% of cortex area). 2-OHE was the most effective in limiting cysts (6.0 ± 0.7% of cortex area, P < 0.05 vs. vehicle-treated cystic rats) and preserving function, in association with suppression of proliferation, apoptosis, and angiogenesis markers. Downregulation of p21 expression and increased expression of Akt, the mammalian target of rapamycin (mTOR), and some of its downstream effectors were significantly reversed by 2-OHE. Thus, 2-OHE limits disease progression in a cystic rodent model. Mechanisms include reduced renal cell proliferation, apoptosis, and angiogenesis. These effects may be mediated, at least in part, by preservation of p21 and suppression of Akt and mTOR. Estradiol metabolites may represent a novel, safe intervention to slow progression of PKD.

Rapamycin: eine neue Therapieoption bei autosomal dominanter polyzystischer Nierenerkrankung (ADPKD)?

Praxis ◽  
2009 ◽  
Vol 98 (25) ◽  
pp. 1511-1516
Author(s):  
Serra ◽  
Wüthrich
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
In Utero ◽  
Polycystic Kidney ◽  
Kausale Therapie ◽  
Polyzystische Nierenerkrankung ◽  
Autosomal Dominant Polycystic Kidney

Die autosomal dominante polyzystische Nierenerkrankung (autosomal dominant polycystic kidney disease, ADPKD) ist charakterisiert durch eine massive Vergrösserung beider Nieren, bedingt durch unzählige Zysten. Die Zystenbildung beginnt bereits in utero und das kontinuierliche Zystenwachstum führt zur Kompression und Zerstörung des nicht-zystischen Nierenparenchyms, sodass schliesslich ein Nierenersatz in der 5. bis 6. Lebensdekade notwendig wird. Bisher gab es keine kausale Therapie, welche das Fortschreiten der Krankheiten aufhält. Tierexperimentelle Daten zeigen, dass die medikamentöse Inhibition eines zentralen Regulators der Zellproliferation, dem so genannten «mammalian target of rapamycin» (mTOR), den Kranheitsverlauf der ADPKD verlangsamen kann. Die vorliegende Übersicht vermittelt einen Einblick in die Erkrankung und in die neue therapeutische Möglichkeit des mTOR Inhibitors Sirolimus, welcher zurzeit in klinischen Studien getestet wird.

scholarly journals Concomitant use of rapamycin and rosiglitazone delays the progression of polycystic kidney disease in Han:SPRD rats: a study of the mechanism of action

2018 ◽  
Vol 314 (5) ◽  
pp. F844-F854 ◽  
Author(s):  
Chunyan Liu ◽  
Hongdong Li ◽  
Xiang Gao ◽  
Ming Yang ◽  
Li Yuan ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Interstitial Fibrosis ◽  
Mammalian Target Of Rapamycin ◽  
Term Treatment ◽  
Peroxisome Proliferator ◽  
Polycystic Kidney ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Long Term Treatment

Attributing to their antiproliferative effect, both rapamycin and peroxisome proliferator-activated receptor-γ (PPARγ) can halt the progression of autosomal dominant polycystic kidney disease (ADPKD). Whether combined use could enhance this effect is unknown. The present study used rapamycin and the PPARγ agonist rosiglitazone concomitantly to observe their combined effects on the proliferation of ADPKD cyst-lining epithelial cells and the progression of ADPKD in Han:SPRD rats. Concomitant use of the two drugs inhibited the proliferation of WT9–12 cells significantly through a superimposition effect. Rosiglitazone inhibited the phosphorylation of mammalian target of rapamycin p70S6K. Concomitant use of rosiglitazone and rapamycin further downregulated the p-p70S6K level. Rosiglitazone also inhibited the phosphorylation of Akt and antagonized the activation of Akt induced by rapamycin. Concomitant use of rosiglitazone and rapamycin significantly retarded the deterioration of renal function, decreased cyst cell proliferation and interstitial fibrosis in Han:SPRD rats. Rapamycin significantly increased cholesterol levels in the blood, whereas rosiglitazone mitigated rapamycin-induced hyperlipidemia. These results indicate that the effects of concomitant use of rosiglitazone and rapamycin in inhibiting the proliferation of WT9–12 cells and delaying the progression of ADPKD in Han:SPRD rats are stronger than those of either drug alone. The present study may provide a new strategy for the long-term treatment of ADPKD.

scholarly journals Klotho supplementation ameliorates blood pressure and renal function in DBA/2-pcy mice, a model of polycystic kidney disease

2020 ◽  
Vol 318 (3) ◽  
pp. F557-F564 ◽  
Author(s):  
Tsuneo Takenaka ◽  
Hiroyuki Kobori ◽  
Tsutomu Inoue ◽  
Takashi Miyazaki ◽  
Hiromichi Suzuki ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Growth Factor ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Mammalian Target Of Rapamycin ◽  
Protein Supplementation ◽  
Target Of Rapamycin ◽  
Polycystic Kidney ◽  
Klotho Protein ◽  
Renal Expression

Klotho interacts with various membrane proteins such as receptors for transforming growth factor-β (TGF-β) and insulin-like growth factor (IGF). Renal expression of klotho is diminished in polycystic kidney disease (PKD). In the present study, the effects of klotho supplementation on PKD were assessed. Recombinant human klotho protein (10 μg·kg−1·day−1) or a vehicle was administered daily by subcutaneous injection to 6-wk-old mice with PKD (DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 mo, mice were killed, and the kidneys were harvested for analysis. Exogenous klotho protein supplementation reduced kidney weight, cystic area, systolic blood pressure, renal angiotensin II levels, and 8-epi-PGF2α excretion ( P < 0.05). Klotho protein supplementation enhanced glomerular filtration rate, renal expression of superoxide dismutase, and klotho itself ( P < 0.05). Klotho supplementation attenuated renal expressions of TGF-β and collagen type I and diminished renal abundance of Twist, phosphorylated Akt, and mammalian target of rapamycin ( P < 0.05). Pathological examination revealed that klotho decreased the fibrosis index and nuclear staining of Smad in PKD kidneys ( P < 0.05). Our data indicate that klotho protein supplementation ameliorates the renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the present results implicate klotho supplementation in the suppression of Akt/mammalian target of rapamycin signaling, slowing cystic expansion. Finally, our findings suggest that klotho protein supplementation attenuated fibrosis at least partly by inhibiting epithelial mesenchymal transition in PKD.

Sign in / Sign up

Export Citation Format

Share Document