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Twist1 in podocytes ameliorates podocyte injury and proteinuria by limiting CCL2-dependent macrophage infiltration
Jiafa Ren, … , Robert F. Spurney, Steven D. Crowley
Jiafa Ren, … , Robert F. Spurney, Steven D. Crowley
Published August 9, 2021
Citation Information: JCI Insight. 2021;6(15):e148109. https://doi.org/10.1172/jci.insight.148109.
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Research Article Nephrology

Twist1 in podocytes ameliorates podocyte injury and proteinuria by limiting CCL2-dependent macrophage infiltration

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Abstract

The transcription factor Twist1 regulates several processes that could impact kidney disease progression, including epithelial cell differentiation and inflammatory cytokine induction. Podocytes are specialized epithelia that exhibit features of immune cells and could therefore mediate unique effects of Twist1 on glomerular disease. To study Twist1 functions in podocytes during proteinuric kidney disease, we employed a conditional mutant mouse in which Twist1 was selectively ablated in podocytes (Twist1-PKO). Deletion of Twist1 in podocytes augmented proteinuria, podocyte injury, and foot process effacement in glomerular injury models. Twist1 in podocytes constrained renal accumulation of monocytes/macrophages and glomerular expression of CCL2 and the macrophage cytokine TNF-α after injury. Deletion of TNF-α selectively from podocytes had no impact on the progression of proteinuric nephropathy. By contrast, the inhibition of CCL2 abrogated the exaggeration in proteinuria and podocyte injury accruing from podocyte Twist1 deletion. Collectively, Twist1 in podocytes mitigated urine albumin excretion and podocyte injury in proteinuric kidney diseases by limiting CCL2 induction that drove monocyte/macrophage infiltration into injured glomeruli. Myeloid cells, rather than podocytes, further promoted podocyte injury and glomerular disease by secreting TNF-α. These data highlight the capacity of Twist1 in the podocyte to mitigate glomerular injury by curtailing the local myeloid immune response.

Authors

Jiafa Ren, Yuemei Xu, Xiaohan Lu, Liming Wang, Shintaro Ide, Gentzon Hall, Tomokazu Souma, Jamie R. Privratsky, Robert F. Spurney, Steven D. Crowley

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Figure 5

Twist1 in podocytes suppresses CCL2 and TNF-α mRNA expression in isolated glomeruli after NTS or ADR injury.

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Twist1 in podocytes suppresses CCL2 and TNF-α mRNA expression in isolate...
(A) mRNA expression for CCL2, TNF-α, IL-17A, IL-6, and CCL5 in isolated Twist1-PKO and WT glomeruli after in vivo NTS exposure (n = 4–5, t test). (B) Representative costaining for nephrin and CCL2 protein in the glomeruli after in vivo NTS exposure and quantitative determination of CCL2-positive cells expressing nephrin in glomeruli (n = 3–5, Student-Newman-Keuls test). (C) mRNA expression for CCL2, TNF-α, IL-6, IL-17A, CCL5, and IFN-γ in isolated Twist1-PKO and WT glomeruli after in vivo ADR injection (n = 4–5, t test). (D) Representative costaining for nephrin and CCL2 protein in the groups after in vivo ADR exposure and quantitative determination of CCL2-positive cells expressing nephrin in glomeruli (n = 3–5, Student-Newman-Keuls test). All t tests were 2 tailed. *P < 0.05, #P < 0.05. Data represent mean ± SEM. White arrowheads indicate double-positive cells. Scale bar: 40 μm. NTS, nephrotoxic serum; ADR, adriamycin; Twist1-PKO, Pod-Cre Twist1fl/fl.

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