Kruppel-like factor 15 (KLF15) is a key regulator of podocyte differentiation

Sandeep K Mallipattu, Ruijie Liu, Feng Zheng, Goutham Narla, Avi Ma'ayan, Steven Dikman, Mukesh K Jain, Moin Saleem, Vivette D'Agati, Paul Klotman, Peter Y Chuang, John C He

Research output: Contribution to journalArticle (Academic Journal)peer-review

74 Citations (Scopus)

Abstract

Podocyte injury resulting from a loss of differentiation is the hallmark of many glomerular diseases. We previously showed that retinoic acid (RA) induces podocyte differentiation via stimulation of the cAMP pathway. However, many podocyte maturity markers lack binding sites for RA-response element or cAMP-response element (CREB) in their promoter regions. We hypothesized that transcription factors induced by RA and downstream of CREB mediate podocyte differentiation. We performed microarray gene expression studies in human podocytes treated with and without RA to identify differentially regulated genes. In comparison with known CREB target genes, we identified Krüppel-like factor 15 (KLF15), a kidney-enriched nuclear transcription factor, that has been previously shown to mediate cell differentiation. We confirmed that RA increased KLF15 expression in both murine and human podocytes. Overexpression of KLF15 stimulated expression of differentiation markers in both wild-type and HIV-1-infected podocytes. Also, KLF15 binding to the promoter regions of nephrin and podocin was increased in RA-treated podocytes. Although KLF15(-/-) mice at base line had minimal phenotype, lipopolysaccharide- or adriamycin-treated KLF15(-/-) mice had a significant increase in proteinuria and podocyte foot process effacement with a reduction in the expression of podocyte differentiation markers as compared with the wild-type treated mice. Finally, KLF15 expression was reduced in glomeruli isolated from HIV transgenic mice as well as in kidney biopsies from patients with HIV-associated nephropathy and idiopathic focal segmental glomerulosclerosis. These results indicate a critical role of KLF15 in mediating podocyte differentiation and in protecting podocytes against injury.

Original languageEnglish
Pages (from-to)19122-35
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number23
DOIs
Publication statusPublished - 1 Jun 2012

Keywords

  • AIDS-Associated Nephropathy
  • Animals
  • Cell Differentiation
  • Cell Line, Transformed
  • DNA-Binding Proteins
  • Gene Expression Regulation
  • HIV-1
  • Humans
  • Kruppel-Like Transcription Factors
  • Mice
  • Mice, Knockout
  • Nuclear Proteins
  • Podocytes
  • Response Elements
  • Transcription Factors
  • Tretinoin
  • Journal Article
  • Research Support, N.I.H., Extramural

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