Krüppel-like factor 15 mediates glucocorticoid-induced restoration of podocyte differentiation markers

Sandeep K. Mallipattu, Yiqing Guo, Monica P. Revelo, Lucia Roa-Peña, Timothy Miller, Jason Ling, Stuart J. Shankland, Agnieszka B. Bialkowska, Victoria Ly, Chelsea Estrada, Mukesh K. Jain, Yuan Lu, Avi Ma'Ayan, Anita Mehrotra, Rabi Yacoub, Edward P. Nord, Robert P. Woroniecki, Vincent W. Yang, John C. He

Research output: Contribution to journalArticlepeer-review

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Abstract

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 treatmentwith glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival inmurine podocytes.We previously determined that Krüppel-like factor 15 (KLF15), a kidney-enriched zinc finger transcription factor, is required for restoringpodocytedifferentiation markers inmice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human andmurine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15. In three independent proteinuric murine models, podocytespecific 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.

Original languageEnglish
Pages (from-to)166-184
Number of pages19
JournalJournal of the American Society of Nephrology
Volume28
Issue number1
DOIs
StatePublished - Jan 2017
Externally publishedYes

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