ZEB2 controls kidney stromal progenitor differentiation and inhibits abnormal myofibroblast expansion and kidney fibrosis
Sudhir Kumar, Xueping Fan, Hila Milo Rasouly, Richa Sharma, David J. Salant, Weining Lu
Sudhir Kumar, Xueping Fan, Hila Milo Rasouly, Richa Sharma, David J. Salant, Weining Lu
View: Text | PDF
Research Article Development Nephrology

ZEB2 controls kidney stromal progenitor differentiation and inhibits abnormal myofibroblast expansion and kidney fibrosis

Abstract

FOXD1+ cell–derived stromal cells give rise to pericytes and fibroblasts that support the kidney vasculature and interstitium but are also major precursors of myofibroblasts. ZEB2 is a SMAD-interacting transcription factor that is expressed in developing kidney stromal progenitors. Here we show that Zeb2 is essential for normal FOXD1+ stromal progenitor development. Specific conditional knockout of mouse Zeb2 in FOXD1+ stromal progenitors (Zeb2 cKO) leads to abnormal interstitial stromal cell development, differentiation, and kidney fibrosis. Immunofluorescent staining analyses revealed abnormal expression of interstitial stromal cell markers MEIS1/2/3, CDKN1C, and CSPG4 (NG2) in newborn and 3-week-old Zeb2-cKO mouse kidneys. Zeb2-deficient FOXD1+ stromal progenitors also took on a myofibroblast fate that led to kidney fibrosis and kidney failure. Cell marker studies further confirmed that these myofibroblasts expressed pericyte and resident fibroblast markers, including PDGFRβ, CSPG4, desmin, GLI1, and NT5E. Notably, increased interstitial collagen deposition associated with loss of Zeb2 in FOXD1+ stromal progenitors was accompanied by increased expression of activated SMAD1/5/8, SMAD2/3, SMAD4, and AXIN2. Thus, our study identifies a key role of ZEB2 in maintaining the cell fate of FOXD1+ stromal progenitors during kidney development, whereas loss of ZEB2 leads to differentiation of FOXD1+ stromal progenitors into myofibroblasts and kidney fibrosis.

Authors

Sudhir Kumar, Xueping Fan, Hila Milo Rasouly, Richa Sharma, David J. Salant, Weining Lu

×

Figure 2

Loss of ZEB2 in FOXD1+ stromal progenitors leads to kidney failure and early mortality.

Options: View larger image (or click on image) Download as PowerPoint
Loss of ZEB2 in FOXD1+ stromal progenitors leads to kidney failure and e...
(A) Expression of ZEB2 protein in Zeb2-cKO mice and wild-type (WT) littermate controls (P0). Compared with WT littermates, there is little ZEB2 (green) expression in the Zeb2-cKO mouse kidney. Scale bar: 50 μm. (B) Zeb2-cKO mice (red line) have shorter life span compared with WT littermate controls (black line). Log-rank test was used for survival analysis: P < 0.05. (C) Smaller body size in a 3-week-old Zeb2-cKO mouse compared with a WT littermate control mouse. (D) Three-week-old Zeb2-cKO mice have paler and smaller kidneys compared with WT littermate controls. (E) The kidney weight of 3-week-old Zeb2-cKO mice is significantly reduced compared with their WT littermate controls. (F) Elevated blood urea nitrogen (BUN) in 3-week-old Zeb2-cKO mice compared with WT littermate controls. Number of animals analyzed: n = 5 per group. Data are expressed as mean ± SEM. ***P < 0.001 by 2-tailed, unpaired Student’s t test (E and F).