Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice

Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Periera-Simon, Simone; Xia, Xiaomei; Korach, Kenneth S.; Berho, Mariana; Elliot, Sharon J.; Karl, Michael

doi:10.1038/ki.2010.398

Cited by 115 publications

(99 citation statements)

References 47 publications

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“…Doublier and colleagues recently developed a mouse model of glomerulosclerosis associated with high testosterone levels. They demonstrated that podocytes express both androgen and estrogen receptors and that in vitro, testosterone can cause podocyte apoptosis, which is blocked by the addition of flutamide (18). In skeletal and cardiac muscle cells, testosterone signals through the mammalian target of rapamycin pathway (19,20).…”

Section: Pathogenesis Of Aas-associated Renal Injurymentioning

confidence: 99%

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Pendergraft

Herlitz

Thornley‐Brown

et al. 2014

Clinical Journal of the American Society of Nephrology

112

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The kidneys can be injured in diverse ways by many drugs, both legal and illegal. Novel associations and descriptions of nephrotoxic effects of common and emerging drugs of abuse have appeared over the past several years. Anabolic androgenic steroids, illicitly used by athletes and others for decades to increase muscle mass and decrease body fat, are emerging as podocyte toxins given recent descriptions of severe forms of FSGS in long-term abusers. Synthetic cannabinoids, a new group of compounds with marijuana-like effects, recently became popular as recreational drugs and have been associated with an atypical form of AKI. 3,4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a widely used synthetic recreational drug with mood-enhancing properties and a constellation of toxicities that can result in death. These toxic effects include hyperthermia, hypotonic hyponatremia due to its arginine vasopressin secretagogue-like effects, rhabdomyolysis, and cardiovascular collapse. Cocaine, a serotonin-norepinephrine-dopamine reuptake inhibitor that serves as an illegal stimulant, appetite suppressant, and anesthetic, also causes vasoconstriction and rhabdomyolysis. Recent adulteration of much of the world's supply of cocaine with levamisole, an antihelminthic agent with attributes similar to but distinct from those of cocaine, appears to have spawned a new type of ANCAassociated systemic vasculitis. This review discusses the nephrotoxic effects of these common and emerging drugs of abuse, of which both community and health care providers should become aware given their widespread abuse. Future investigation into pathogenetic mechanisms associated with these drugs is critical and may provide a window into ways to lessen and even prevent the nephrotoxic effects of these drugs of abuse and perhaps allow a deeper understanding of the nephrotoxicities themselves.

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Section: Pathogenesis Of Aas-associated Renal Injurymentioning

confidence: 99%

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Pendergraft

Herlitz

Thornley‐Brown

et al. 2014

Clinical Journal of the American Society of Nephrology

112

View full text Add to dashboard Cite

show abstract

“…Podocytes express hormone receptors, including for progesterone and estrogen, and 17b-estradiol has been shown to stabilize actin cytoskeleton and protect podocytes against oxidant-induced injury. [52][53][54] The diversity of the identified hits signifies the possibility of identifying a number of relevant signaling pathways through the presented phenotypic assay that may be targeted for protecting podocytes from injury.…”

Section: Discussionmentioning

confidence: 99%

A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules

Lee¹,

Khan²,

Faridi³

et al. 2015

Journal of the American Society of Nephrology

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Podocyte injury and loss mark an early step in the pathogenesis of various glomerular diseases, making these cells excellent targets for therapeutics. However, cell-based high-throughput screening assays for the rational development of podocyte-directed therapeutics are currently lacking. Here, we describe a novel high-content screening-based phenotypic assay that analyzes thousands of podocytes per assay condition in 96-well plates to quantitatively measure dose-dependent changes in multiple cellular features. Our assay consistently produced a Z9 value .0.44, making it suitable for compound screening. On screening with .2100 pharmacologically active agents, we identified 24 small molecules that protected podocytes against injury in vitro (1% hit rate). Among the identified hits, we confirmed an b1-integrin agonist, pyrintegrin, as a podocyte-protective agent. Treatment with pyrintegrin prevented damage-induced decreases in F-actin stress fibers, focal adhesions, and active b1-integrin levels in cultured cells. In vivo, administration of pyrintegrin protected mice from LPS-induced podocyte foot process effacement and proteinuria. Analysis of the murine glomeruli showed that LPS administration reduced the levels of active b1 integrin in the podocytes, which was prevented by cotreatment with pyrintegrin. In rats, pyrintegrin reduced peak proteinuria caused by puromycin aminonucleoside-induced nephropathy. Our findings identify pyrintegrin as a potential therapeutic candidate and show the use of podocyte-based screening assays for identifying novel therapeutics for proteinuric kidney diseases.

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“…Interestingly, similar pathways have recently been shown to be active in podocytes: podocytes isolated, immortalized, and subsequently analyzed in vitro were observed to show estrogen-induced modulation of TGFβ-and MAPKpathways [57]. Doublier and colleagues demonstrated that this mechanism also leads to a protection of podocytes against transforming growth factor beta 1 (TGFβ1)-or tumor necrosis factor alpha (TNFα)-induced apoptosis in vitro and in vivo, while testosterone induces podocyte apoptosis by signaling via androgen receptors [58]. Unpublished data from our group show a corresponding estrogen-induced protection of podocytes in the model of puromycin-induced apoptosis.…”

Section: Cellular Pathways Of Sexual Hormones and Selective Estrogenmentioning

confidence: 99%

The influence of gender and sexual hormones on incidence and outcome of chronic kidney disease

et al. 2011

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It has long been known that the female sex is associated with a better clinical outcome in chronic renal diseases. Although many experimental, clinical, and epidemiological studies in adults have attempted to explain the difference in disease progression between females and males, a definitive understanding of the underlying mechanisms is still lacking. Hormone-modulating therapies are being increasingly used for various indications (such as post-menopausal hormone replacement, estrogen- or androgen-receptor antagonists for cancer therapy). Therefore, a deeper knowledge of the interaction between sexual hormones and progression of kidney disease is important, as hormone-modulating therapy for non-renal indication may influence both kidney structure and function. In addition, specific modulation of the sexual hormone system, such as the use of selective estrogen receptor modulators, may represent a therapeutic option for patients with renal diseases. Although conclusive data on this topic in the pediatric population are still lacking, the aim of this review is to familiarize pediatric nephrologists with gender-specific differences in renal physiology, pathophysiology, and the progression of kidney diseases. Experimental models that analyze the effects of sexual hormones on renal structure and function are discussed. It is hoped that this review will stimulate researchers to focus on pediatric studies that will provide a deeper insight into the interaction of gender hormones and the kidney both before and during puberty.

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Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice

Cited by 115 publications

References 47 publications

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules

The influence of gender and sexual hormones on incidence and outcome of chronic kidney disease

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