Krüppel-like factor 4 is a negative regulator of STAT3-induced glomerular epithelial cell proliferation.

Autor:	Estrada CC; Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA., Paladugu P; Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA., Guo Y; Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA., Pace J; Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA., Revelo MP; Department of Pathology, University of Utah, Salt Lake City, Utah, USA., Salant DJ; Division of Nephrology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA., Shankland SJ; Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA., D'Agati VD; Department of Pathology, Columbia University, New York, New York, USA., Mehrotra A; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Renal Section, James J. Peters VA Medical Center, New York, New York, USA., Cardona S; Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA., Bialkowska AB; Division of Gastroenterology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA., Yang VW; Division of Gastroenterology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA., He JC; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Renal Section, James J. Peters VA Medical Center, New York, New York, USA., Mallipattu SK; Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA.; Renal Section, Northport VA Medical Center, Northport, New York, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2018 Jun 21; Vol. 3 (12). Date of Electronic Publication: 2018 Jun 21 (Print Publication: 2018).
DOI:	10.1172/jci.insight.98214
Abstrakt:	Pathologic glomerular epithelial cell (GEC) hyperplasia is characteristic of both rapidly progressive glomerulonephritis (RPGN) and subtypes of focal segmental glomerulosclerosis (FSGS). Although initial podocyte injury resulting in activation of STAT3 signals GEC proliferation in both diseases, mechanisms regulating this are unknown. Here, we show that the loss of Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, enhances GEC proliferation in both RPGN and FSGS due to dysregulated STAT3 signaling. We observed that podocyte-specific knockdown of Klf4 (C57BL/6J) increased STAT3 signaling and exacerbated crescent formation after nephrotoxic serum treatment. Interestingly, podocyte-specific knockdown of Klf4 in the FVB/N background alone was sufficient to activate STAT3 signaling, resulting in FSGS with extracapillary proliferation, as well as renal failure and reduced survival. In cultured podocytes, loss of KLF4 resulted in STAT3 activation and cell-cycle reentry, leading to mitotic catastrophe. This triggered IL-6 release into the supernatant, which activated STAT3 signaling in parietal epithelial cells. Conversely, either restoration of KLF4 expression or inhibition of STAT3 signaling improved survival in KLF4-knockdown podocytes. Finally, human kidney biopsy specimens with RPGN exhibited reduced KLF4 expression with a concomitant increase in phospho-STAT3 expression as compared with controls. Collectively, these results suggest the essential role of KLF4/STAT3 signaling in podocyte injury and its regulation of aberrant GEC proliferation.
Databáze:	MEDLINE
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