DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity
Aili Cao, … , Katalin Susztak, Lewis Kaufman
Aili Cao, … , Katalin Susztak, Lewis Kaufman
Published May 17, 2021
Citation Information: J Clin Invest. 2021;131(10):e141279. https://doi.org/10.1172/JCI141279.
View: Text | PDF
Research Article Nephrology

DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity

Abstract

Dachshund homolog 1 (DACH1), a key cell-fate determinant, regulates transcription by DNA sequence–specific binding. We identified diminished Dach1 expression in a large-scale screen for mutations that convert injury-resistant podocytes into injury-susceptible podocytes. In diabetic kidney disease (DKD) patients, podocyte DACH1 expression levels are diminished, a condition that strongly correlates with poor clinical outcomes. Global Dach1 KO mice manifest renal hypoplasia and die perinatally. Podocyte-specific Dach1 KO mice, however, maintain normal glomerular architecture at baseline, but rapidly exhibit podocyte injury after diabetes onset. Furthermore, podocyte-specific augmentation of DACH1 expression in mice protects from DKD. Combined RNA sequencing and in silico promoter analysis reveal conversely overlapping glomerular transcriptomic signatures between podocyte-specific Dach1 and Pax transactivation-domain interacting protein (Ptip) KO mice, with upregulated genes possessing higher-than-expected numbers of promoter Dach1-binding sites. PTIP, an essential component of the activating histone H3 lysine 4 trimethylation (H3K4Me3) complex, interacts with DACH1 and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increases promoter H3K4Me3. These findings reveal that in DKD, diminished DACH1 expression enhances podocyte injury vulnerability via epigenetic derepression of its target genes.

Authors

Aili Cao, Jianhua Li, Morad Asadi, John M. Basgen, Bingbing Zhu, Zhengzi Yi, Song Jiang, Tomohito Doke, Osama El Shamy, Niralee Patel, Paolo Cravedi, Evren U. Azeloglu, Kirk N. Campbell, Madhav Menon, Steve Coca, Weijia Zhang, Hao Wang, Ke Zen, Zhihong Liu, Barbara Murphy, John C. He, Vivette D. D’Agati, Katalin Susztak, Lewis Kaufman

×

Figure 4

Podocyte-specific Dach1 KO mice, after onset of type I DM, exhibit severe podocyte injury with rapid progression to ESRD.

Options: View larger image (or click on image) Download as PowerPoint
Podocyte-specific Dach1 KO mice, after onset of type I DM, exhibit sever...
(A) Double-immunofluorescent staining for DACH1 and the podocyte nuclear marker WT1. Podocyte-specific Dach1 KO mice show absent podocyte DACH1 expression, whereas control littermates exhibit robust podocyte DACH1 expression. Scale bars: 50 μm (low power); 20 μm (high power). (B) Blood glucose levels of mice 2 weeks after completion of STZ administration. Circles, male mice; triangles, female mice. (C) Spot urine protein:creatinine ratios of mice collected 4 weeks after onset of type I DM. *P < 0.01. (D) PAS-stained kidney sections. Nondiabetic age-matched podocyte-specific Dach1 KO mice have normal appearing glomerular morphology (top row). Age-matched control mice also demonstrate normal glomerular structure 1 month after onset of type I DM (second row). Podocyte-specific Dach1 KO mice, however, also sacrificed 1 month after DM onset, showed severe FSGS with evidence of podocyte loss and detachment and diffuse tubular proteinaceous casts (third row). In fact, several mice by this time point had progressed to DGGS consistent with ESRD (bottom row). Scale bars: 100 μm (low power); 40 μm (medium power); 20 μm (high power). (E) Podocyte-specific Dach1 KO mice under basal conditions demonstrate open capillary loops with delicate foot processes (upper left). Control mice also show normal podocyte morphology 1 month after onset of type I DM (upper right). Diabetic podocyte-specific Dach1 KO mice, however, demonstrate catastrophic podocyte injury characterized by total disruption of actin cytoskeletal structure (lower left) with loss of primary and secondary processes and complete foot-process effacement (lower middle). Several mice showed DGGS with severe podocyte loss and a largely denuded GBM (lower right). (F) Quantification of podocyte numbers. n = 3 mice per group with 20 glomeruli analyzed per mouse. *P < 0.0001, 2-tailed Student’s t test.