ArticleAmerican journal of nephrology2012
Mineralocorticoid receptor-dependent proximal tubule injury is mediated by a redox-sensitive mTOR/S6K1 pathway.
Article in American journal of nephrology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 39 citations in OpenAlex.
- Pathogenesis and Therapeutic Perspectives of Tubular Injury in Diabetic Kidney Disease: An Update.Biomedicines · 2025Review
- The mineralocorticoid receptor in diabetic kidney disease.American journal of physiology. Renal physiology · 2024Review
- Association of triglyceride glucose index with the risk of acute kidney injury in patients with coronary revascularization: a cohort study.Diabetology & metabolic syndrome · 2024Article
- Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II.International journal of molecular sciences · 2023Article
- Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms.Frontiers in endocrinology · 2023Review
- Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase.Theranostics · 2023Article
- Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications.Physiological reviews · 2022Review
- Cardiovascular and Renal Outcomes with Finerenone, a Selective Mineralocorticoid Receptor Antagonist.Cardiology and therapy · 2022Review
- Mechanisms contributing to adverse outcomes of COVID-19 in obesity.Molecular and cellular biochemistry · 2022Review
- Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin.American journal of physiology. Endocrinology and metabolism · 2021Article
- mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner.Endocrinology · 2020Article
- Aldosterone Modulates the Mechanistic Target of Rapamycin Signaling in Male Mice.Endocrinology · 2019Article
- Anti-Diabetogenic Properties of Mineralocorticoid Receptor Antagonists: Implications for Enhanced Safety and Efficacy of Post-Transplantation Pharmacotherapies.Medical science monitor : international medical journal of experimental and clinical research · 2019Article
- Renal miR-148b is associated with megalin down-regulation in IgA nephropathy.Bioscience reports · 2018Article
- Insulin Resistance in Kidney Disease: Is There a Distinct Role Separate from That of Diabetes or Obesity?Cardiorenal medicine · 2017Review
- Overexpressed cyclophilin B suppresses aldosterone-induced proximal tubular cell injury both in vitro and in vivo.Oncotarget · 2016Article
- Review
- Overnutrition, mTOR signaling, and cardiovascular diseases.American journal of physiology. Regulatory, integrative and comparative physiology · 2014Review
- A role for the age-dependent loss of α(E)-catenin in regulation of N-cadherin expression and cell migration.Physiological reports · 2014Article
- Resistance to insulin and kidney disease in the cardiorenal metabolic syndrome; role for angiotensin II.Molecular and cellular endocrinology · 2013Review
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
BACKGROUND/
aimsThe mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics.
methodsAccordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks.
resultsRen2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin.
conclusionsThereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.
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