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J Am Soc Nephrol. 2017 Jan;28(1):166-184. doi: 10.1681/ASN.2015060672. Epub 2016 Jun 10.

Krüppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers.

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Division of Nephrology, Departments of Medicine and
Division of Nephrology, Departments of Medicine and.
Department of Pathology, University of Utah, Salt Lake City, Utah.
Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Division of Gastroenterology, Department of Medicine, Stony Brook University, Stony Brook, New York.
Case Cardiovascular Institute Research Institute, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
Department of Pharmacology and Systems Therapeutics and.
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and.
Pediatrics and.
Renal Section, James J. Peters Veterans Affairs Medical Center, New York, New York.


Podocyte injury is the inciting event in primary glomerulopathies, such as minimal change disease and primary FSGS, and glucocorticoids remain the initial and often, the primary treatment of choice for these glomerulopathies. Because inflammation is not readily apparent in these diseases, understanding the direct effects of glucocorticoids on the podocyte, independent of the immunomodulatory effects, may lead to the identification of targets downstream of glucocorticoids that minimize toxicity without compromising efficacy. Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. We previously determined that Krüppel-like factor 15 (KLF15), a kidney-enriched zinc finger transcription factor, is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. Thus, these studies identify the critical role of KLF15 in mediating the salutary effects of glucocorticoids in the podocyte.


focal segmental glomerulosclerosis; glucocorticoid; minimal change disease; podocyte

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