Inappropriate activation of the renin angiotensin system (RAS) makes a critical contribution to the progression of chronic kidney disease (CKD). However, the effects of the RAS effector angiotensin (Ang) II on renal damage are tissue-specific. Stimulating type 1 angiotensin (AT1) receptors in the kidney drives blood pressure elevation and renal injury. By contrast, we have recently established that activating AT1 receptors directly on T lymphocytes suppresses pro-inflammatory Th1 cytokines and protects the kidney. Like angiotensin (Ang II), the transcription factor Twist1 acts in kidney cells to driv renal fibrosis but in immune cells to suppress NF-?b-dependent cytokine induction. To explain these analogous actions of Ang II and Twist1, we have discovered that Ang II induces Twist1 expression in macrophages and T lymphocytes. Nevertheless, in our new preliminary studies, Twist1 in T cells promotes blood pressure elevation and albuminuria in the Ang II-dependent hypertension model. This finding is completely unexpected based on the published literature that emphasizes cytokine suppression by Twist1 in T cells. Resolving this paradox, NF- ?B activation also drives transcription of TGF-? 9, a key effector cytokine of CD4+CD25+ T regulatory cells whose adoptive transfer can blunt the hypertensive response. We find that Twist1 in T cells limits the emergence of these CD4+CD25+ T cells following NF-?B stimulation. We therefore hypothesize that Twist1 in T cells promotes hypertension and renal injury during RAS activation by suppressing T regulatory cell functions. To test this hypothesis, we will subject mice lacking Twist1 solely in T cells to models of RAS- dependent hypertension and kidney damage. Whereas TGF-? in T lymphocytes mediates T regulatory cell functions, TGF-? in macrophages drives kidney fibrosis during RAS activation. Consistent with this notion, in our preliminary studies, Twist1-deficiency in macrophages permits exaggerated TGF-? and TNF-? expression, leading to augmented RAS-dependent kidney damage and fibrosis. However, we now find that these same cytokines can induce several Wnt ligand isoforms in kidney epithelial cells and that blocking Porcupine (PORC)-dependent secretion of these Wnts dramatically attenuates the extent of kidney damage and fibrosis. Thus, we posit that Twist1 in macrophages protects the kidney from injury and fibrosis by limiting cytokine-dependent Wnt generation in kidney epithelial cells. We will test this possibility using unpublished models of macrophage-specific Twist1 deficiency and kidney-specific PORC deficiency in conjunction with our kidney cross-transplantation strategy. Collectively, our studies will define for the first time the contribution of Twist1 in hematopoietic cell populations to blood pressure regulation and will discriminate novel mechanisms through which Twist1 modulates kidney damage and fibrosis. Given the importance of Twist1 not only to fibrosis but also to tumor metastasis, establishing these cell-specific actions of Twist1 in vivo will be critical to allow targeting of this pathway i patients with hypertension, tissue fibrosis, and cancer.
Inappropriate activation of the renin angiotensin system (RAS) accelerates the progression of chronic kidney disease. This proposal explores how the transcription factor Twist1 modulates RAS-mediated renal damage by regulating a subset of T lymphocytes (Th1 cells). Understanding how Th1 immune responses influence angiotensin II-induced kidney injury should lead to more effective strategies for preventing progressive chronic kidney disease.
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