Krüppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers.
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.
Division of Nephrology, Departments of Medicine and sandeep.mallipattu@stonybrookmedicine.edu.
Sandeep K
SK
Mallipattu
Division of Nephrology, Departments of Medicine and.
Yiqing
Y
Guo
Department of Pathology, University of Utah, Salt Lake City, Utah.
Monica P
MP
Revelo
Division of Nephrology, Departments of Medicine and.
Lucia
L
Roa-Peña
Division of Nephrology, Departments of Medicine and.
Timothy
T
Miller
Division of Nephrology, Departments of Medicine and.
Jason
J
Ling
Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Stuart J
SJ
Shankland
Division of Gastroenterology, Department of Medicine, Stony Brook University, Stony Brook, New York.
Agnieszka B
AB
Bialkowska
Division of Nephrology, Departments of Medicine and.
Victoria
V
Ly
Division of Nephrology, Departments of Medicine and.
Chelsea
C
Estrada
Case Cardiovascular Institute Research Institute, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
Mukesh K
MK
Jain
Case Cardiovascular Institute Research Institute, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
Yuan
Y
Lu
Department of Pharmacology and Systems Therapeutics and.
Avi
A
Ma'ayan
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and.
Anita
A
Mehrotra
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and.
Rabi
R
Yacoub
Division of Nephrology, Departments of Medicine and.
Edward P
EP
Nord
Pediatrics and.
Robert P
RP
Woroniecki
Division of Gastroenterology, Department of Medicine, Stony Brook University, Stony Brook, New York.
Vincent W
VW
Yang
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.|Renal Section, James J. Peters Veterans Affairs Medical Center, New York, New York.
John C
JC
He
D000293:Adolescent; D000328:Adult; D000818:Animals; D000943:Antigens, Differentiation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002648:Child; D004268:DNA-Binding Proteins / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008297:Male; D051379:Mice; D008875:Middle Aged; D009402:Nephrosis, Lipoid / Q000276:immunology; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects*; D014157:Transcription Factors / Q000502:physiology*; D055815:Young Adult
D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D003907:Dexamethasone
focal segmental glomerulosclerosis; glucocorticoid; minimal change disease; podocyte