Cytokine Signaling in Renal Fibrosis

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DESCRIPTION (provided by applicant): With funding from this grant, we have achieved several key discoveries in TGF-beta signaling that redirected our research focus from well-documented, glomerular and interstitial fibrosis outcomes in advanced renal disease to novel proapoptotic and growth inhibitory TGF-beta signaling in podocytes. In this revised renewal application, we propose that TGF-beta contributes to podocyte depletion during early stages of glomerular injury. Our new hypothesis states that negative regulation of Gadd45b by Smad2 silences proapoptotic p38 MARK in the context of moderate physiological TGF-0 activity. In contrast, when TGF-(3 activity exceeds a critical threshold, negative regulation of Gadd45b by Smad2 becomes suppressed resulting in derepression of Gadd45b. Gadd45b selectively activates the proapoptotic p38 MARK pathway if its intracellular concentrations exceed a critical signaling threshold. To test this hypothesis, we propose three SPECIFIC AIMS: 1) Determine whether Smad2 functions as negative regulator of proapoptotic Gadd45b and p38/JNK MARK and podocyte apoptosis, and examine whether Smad2 thereby protects against podocyte depletion and glomerulosclerosis. 2) Determine whether Gadd45b mediates activation of proapoptotic p38/JNK MARK signaling and podocyte apoptosis, and examine whether Gadd45b-deficiency prevents podocyte depletion and FSGS in Cd2ap-/- mice. 3) Determine whether an abundance threshold of Gadd45b protein in podocytes is sufficient to specify effective activation of proapoptotic p38/JNK pathways to mediate apoptosis, using doxycycline-inducible tritation of abundance of Gadd45b protein in conditionally-immortalized podocytes. In the long-term, this work will elucidate molecular signaling mechanisms determining specific, contextdependent cellular responses, such as apoptosis and growth arrest, that may be triggered by different concentrations of TGF-beta in different cell types subject to injury in chronic progressive renal disease.