Renoprotective Effect of KLF2 on Glomerular Endothelial Dysfunction in Hypertensive Nephropathy.

Eunjin Bae,Saram Lee,Dong-Jun Park,Jong-Joo Moon,Mi-Yeon Yu,Seung-Hee Yang,Ji-Eun Kim,Sang-Woong Han,Yon-Su Kim

doi:10.3390/cells11050762

Abstract

Kruppel-like factor 2 (KLF2) regulates endothelial cell metabolism; endothelial dysfunction is associated with hypertension and is a predictor of atherosclerosis development and cardiovascular events. Here, we investigated the role of KLF2 in hypertensive nephropathy by regulating KLF2 expression in human primary glomerular endothelial cells (hPGECs) and evaluating this expression in the kidney tissues of a 5/6 nephrectomy mouse model as well as patients with hypertension. Hypertension-mimicking devices and KLF2 siRNA were used to downregulate KLF2 expression, while the expression of KLF2 was upregulated by administering simvastatin. After 4 mmHg of pressure was applied on hPGECs for 48 h, KLF2 mRNA expression decreased, while alpha-smooth muscle actin (αSMA) mRNA expression increased. Apoptosis and fibrosis rates were increased under pressure, and these phenomena were aggravated following KLF2 knockdown, but were alleviated after simvastatin treatment; additionally, these changes were observed in angiotensin II, angiotensin type-1 receptor (AT1R) mRNA, and interleukin-18 (IL-18), but not in angiotensin type-2 receptor mRNA. Reduced expression of KLF2 in glomerular endothelial cells due to hypertension was found in both 5/6 nephrectomy mice and patients with hypertensive nephropathy. Thus, our study demonstrates that the pressure-induced apoptosis and fibrosis of glomerular endothelial cells result from angiotensin II, AT1R activation, and KLF2 inhibition, and are associated with IL-18.

Highlights

We investigated whether angiotensin II, one of the key factors in the mechanism of hypertensive nephropathy, is produced in human primary glomerular endothelial cells (hPGECs) through mechanical pressurization via rotational force
Study, we II expression was increased increased in in hPGECs hPGECs through mechanical pressurization via rotational force, which led to increases apoptothrough mechanical pressurization via rotational force, which led to increases inin apoptosis, fibrosis, and proinflammatory markers via the angiotensin type-1 receptor (AT1R)-dominant pathway. These results were alleviated by Kruppel-like factor 2 (KLF2) upregulation and worsened by KLF2 knockdown, suggesting that pressure-induced apoptotic and fibrotic injuries in hPGECs are mediated by KLF2
We found that the expression of KLF2 in glomerular endothelial cells was decreased by hypertensive kidney injury

Summary

Introduction

A total of 17 members of the KLF family have been reported, and different functions have been identified depending on the members in the kidney. KLF15 is a critical regulator of podocyte differentiation and is protective against podocyte injury [6,7,8]. KLF2 mediates the functions of various types of cells, among which its role is crucial in endothelial cells, and it plays a pivotal role in quiescence, shear stress regulation, homeostasis, and vasculogenesis [9,10]. KLF2 is activated by laminar shear stress and inhibits endothelial inflammation [11,12,13] as well as thrombosis [14,15,16]. KLF2 expression is reduced by disturbed stress in branched points of blood vessels with atheroprone flow patterns [17,18], resulting in endothelial dysfunction [19,20]

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