Because the diagnosis of autosomal dominant polycystic kidney disease (ADPKD) cannot be excluded until age 40, many ADPKD patients are veterans. The objective of this proposal is to define therapeutic potential of targeting C3 (the axial component of complement pathway) in ADPKD. In line with paradigm shifts resulting from discoveries of novel essential roles of local C3 production, our studies point to intra-renal production of C3 as a regulator of a pathway that dictates the pace of renal cystogenesis. We formulated this hypothesis based on our genome-wide expression analyses of kidneys with rapid vs slow pace of cystogenesis in a PKD model. We supported this hypothesis by demonstrating: (i) presence of both C3 mRNA and protein in renal tubular cells that line ADPKD and autosomal recessive (AR) PKD cysts and the ability of these cells to activate C3;(ii) increased renal content of biologically active C3 split products i ARPKD and ADPKD and their models;(iii) strong correlation between renal C3 expression and pace of renal cystogenesis in a PKD model and C3 hypoactive gene variant with the disease progression among ADPKD patients;and (iv) significant protective effect of C3 deficiency on renal cystogenesis in genetic PKD models. While C3 may act through different pathways, we have found consistent association of accelerated cystogenesis specifically with the pathway regulated by complement receptor CR3. CR3 (or Mac- 1), a major receptor for C3 fragment iC3b, which is highly abundant in cystic kidneys, plays a central role in differentiation, attachment and survival of monocytes/macrophages. While we have identified C3, macrophage marker CD14 and C3-inducible factor MCP-1 as candidate predictors of PKD outcomes, others have demonstrated that macrophage depletion attenuates cystogenesis in orthologous models of ADPKD by reducing the proliferation of cystic tubules. CR3 may also induce pro-cystogenic TNF release and directly activate c-Src in renal tubule cells. Since renal tubule cells produce and activate C3 when fluid flow is absent we suggest that the C3 effects in PKD increase as cystic tubules dilate, forming a vicious cystogenic cycle. Specifically, we hypothesize that C3 pathway activation accelerates cyst formation in ADPKD through a CR3 dependent process. We address this hypothesis in three inter-related aims: 1) Dissect mechanisms underlying cystogenic effects of C3 production on Pkd1 pathway;2) Determine effects of renal tubule-derived C3 in the pathogenesis of ADPKD.;and 3) Determine the role of complement component receptor CR3 (or Mac1) in Pkd1-induced cystogenesis. Objectives of these Aims will be accomplished by integrating: (i) highly innovative study design of interrogating novel regulatory mechanisms of renal cystogenesis with (ii) generation of novel state of the art reagents (e.g., for conditional C3 targeting). Achieving the proposed aims will allow integration of existing knowledge by linking established and novel cystogenic pathways to the C3-CR3 nexus. The proposed studies represent the next step for attaining our long-term goal of developing a safe C3-based therapy for ADPKD and other renal disorders.
Our initial studies point to local intra-renal production of complement component 3 (C3), an axial component of complement pathway, as regulator of cystogenic pathway that dictates the pace of ADPKD progression. Therefore, we propose to establish key relationships of C3 effects in the pathogenesis of ADPKD and provide foundation for pre-clinical ADPKD studies targeting C3-regulated pathways.
|Chumley, Phillip; Zhou, Juling; Mrug, Sylvie et al. (2018) Truncating PKHD1 and PKD2 mutations alter energy metabolism. Am J Physiol Renal Physiol :|
|Harms, James; Khawaja, Ayaz; Taylor, Maria et al. (2017) Recovery of methotrexate-induced anuric acute kidney injury after glucarpidase therapy. SAGE Open Med Case Rep 5:2050313X17705050|
|Torres, Vicente E; Chapman, Arlene B; Devuyst, Olivier et al. (2017) Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 377:1930-1942|
|Mrug, Michal; Sanders, Paul W (2013) Beware the low HDAC11: males at risk for ischemic kidney injury. Am J Physiol Renal Physiol 305:F973-4|