Hypertension is known to be responsible for a reduction in the number of functional nephrons of glomeruli due to fibrosis, which develops into a chronic kidney disease. We propose a system that induces pressure through centrifugal force to mimic in vivo hypertensive environment in glomeruli. And we research the podocytes under pressure in perspective of Krüppel-like factor 15 (KLF15), which may be involved in the progression of kidney fibrosis.

Human primary podocytes, those extracted from glomeruli, were cultured using the devices under different pressure levels (4 and 8 mmHg) and exposure times (3, 48, and 72 hours).Levels of KLF15 and fibronectin were compared with the podocytes those cultured in a static condition. Intrarenal mRNA expressions of podocyte-associated molecules were also quantified. After adding pressure, changes of KLF15 and fibronetin expressions were examines in the level of angiotensin receptor blocker (ARB) treatment. Further analysis was conducted in both mouse chronic renal failure model and humans with biopsy proven hypertensive nephropathy.

We confirmed that fibrosis is induced using the propose pressuring system through increased expression of fibronectin with increased pressure manner. The expression of KLF15 decreased as the pressure level increased.Expressions of podocyte-associated molecules showed inversely correlation, which indicate that podocytes lost their functionalities and de-differentiated. Treatment with an ARB reduced the fibrosis with recovery of KLF15 expression. In mouse chronic renal failure model, senescence markers including CCN1 and β-galactosidase were increased. Increases of fibronectin and decreases of KLF15 were detected. In the human kidney with biopsy proven hypertensive nephropathy, KLF15 expression were significantly lower than in normal controls.

In this study, we were able to induce podocyte fibrosis by applying centrifugal force driven pressure, and demonstrated that KLF15 contributes in suppression of the fibrosis. The proposed system may serve as useful tool for mechanistic studies for kidney fibrosis, and the mechanism of KLF15 may be applied as a potential therapeutic target in hypertension-associated kidney fibrosis.

CITATION INFORMATION: Yu M., Kim Y., Lee H., Lee J., Cha R., Lee C., Kim Y., Yang S. Krüppel-Like Factor 15 is a Key Suppressor of the Glomerular Epithelial Cell Fibrosis under Centrifugal Force Driven Pressure Am J Transplant. 2017;17 (suppl 3).

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