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

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 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.

The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis

“…Along with others, we previously demonstrated that KLF15 is ubiquitously expressed in several cell types in the mouse and human kidney (podocytes, mesangial cells, tubular cells, fibroblasts, and endothelial cells) (Figure 1A) 21, 22 . Furthermore, since resident fibroblasts, mesangial cells, and pericytes in the kidney are a major source of kidney fibrosis 23 , we initially chose to examine the role of KLF15 specifically in these cells in murine models of kidney fibrosis.…”

“…Since KLF15 is expressed in the glomerular compartment as well as the tubulointerstitial compartment 21, 22 , we specifically measured KLF15 expression in RNA extracted from laser capture microdissected tubulointerstitial kidney biopsies with arterial hypertension and DKD as compared to healthy donor subjects 28, 29 (Figure 11A, 11B). To further validate these findings, we measured KLF15 and α-SMA expression by immunostaining de-identified kidney biopsies with early and late-stage DKD as compared to healthy donor subjects.…”

“…To date, this is the first study to utilize the renal stromal progenitor-specific knockdown of Klf15 and confirm a critical role of KLF15 in the regulation of myofibroblast proliferation. Since KLF15 is also expressed in other cell types in the kidney 22 , the effects of KLF15 expression in non-stromal cells cannot be neglected. As such, future studies will need to focus on investigating whether changes in KLF15 expression in other kidney cells (i.e.…”

“…Immunofluorescence was performed as recently reported 22 . In brief, blank slides were initially baked overnight at 55–60°C and were then processed as pre viously described.…”

Focal Segmental Glomerulosclerosis

“…Recently, it has been shown that the effects of glucocorticoids may be mediated by Krüppel factor 15, a zinc finger transcription factor (57,58). In a recent retrospective case series involving 476 subjects, the use of glucocorticoids and/or cyclosporin was associated with improved outcomes compared to no immunosuppression, with a hazard ratio of 0.49 (95% CI, 0.28 to 0.86) for ESRD whereas the use of cyclosporine with or without glucocorticoids was not associated with benefit HR 0.42 (95% CI, 0.15 to 1.18) (59).…”