Chronic kidney disease induces left ventricular overexpression of the pro-hypertrophic microRNA-212.

Abstract

Chronic kidney disease (CKD) is a public health problem that increases the risk of cardiovascular morbidity and mortality. Heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction is a common cardiovascular complication of CKD. MicroRNA-212 (miR-212) has been demonstrated previously to be a crucial regulator of pathologic LVH in pressure-overload-induced heart failure via regulating the forkhead box O3 (FOXO3)/calcineurin/nuclear factor of activated T-cells (NFAT) pathway. Here we aimed to investigate whether miR-212 and its hypertrophy-associated targets including FOXO3, extracellular signal-regulated kinase 2 (ERK2), and AMP-activated protein kinase (AMPK) play a role in the development of HFpEF in CKD. CKD was induced by 5/6 nephrectomy in male Wistar rats. Echocardiography and histology revealed LVH, fibrosis, preserved systolic function, and diastolic dysfunction in the CKD group as compared to sham-operated animals eight and/or nine weeks later. Left ventricular miR-212 was significantly overexpressed in CKD. However, expressions of FOXO3, AMPK, and ERK2 failed to change significantly at the mRNA or protein level. The protein kinase B (AKT)/FOXO3 and AKT/mammalian target of rapamycin (mTOR) pathways are also proposed regulators of LVH induced by pressure-overload. Interestingly, phospho-AKT/total-AKT ratio was increased in CKD without significantly affecting phosphorylation of FOXO3 or mTOR. In summary, cardiac overexpression of miR-212 in CKD failed to affect its previously implicated hypertrophy-associated downstream targets. Thus, the molecular mechanism of the development of LVH in CKD seems to be independent of the FOXO3, ERK1/2, AMPK, and AKT/mTOR-mediated pathways indicating unique features in this form of LVH.

• Authors: Márta Sárközy, Renáta Gáspár, Ágnes Zvara, Andrea Siska, Bence Kővári, Gergő Szűcs, Fanni Márványkövi, Mónika G Kovács, Petra Diószegi, László Bodai, Nóra Zsindely, Márton Pipicz, Kamilla Gömöri, Krisztina Kiss, Péter Bencsik, Gábor Cserni, László G Puskás, Imre Földesi, Thomas Thum, Sándor Bátkai, Tamás Csont
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 1302 (02 04 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 30718600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FOXO3 protein, rat
• Forkhead Box Protein O3
• MicroRNAs
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Biopsy
• Disease Models, Animal
• Echocardiography
• Forkhead Box Protein O3 (genetics, metabolism)
• Gene Expression
• Gene Expression Profiling
• Hypertrophy, Left Ventricular (diagnosis, etiology)
• MicroRNAs (genetics)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Myocytes, Cardiac
• Phosphorylation
• Rats
• Renal Insufficiency, Chronic (complications)
• Signal Transduction