This grant application addresses the role of complement component 3 (C3), an axial component of complement pathway, in the pathogenesis of autosomal recessive polycystic kidneys disease (ARPKD), the most severe form of polycystic kidney disease (PKD). 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 cystogenic pathway that dictates the pace of ARPKD progression. We formulated this hypothesis based on our genome-wide expression analyses of kidneys with rapid verses slow pace of cystogenesis in Cys1cpk/cpk model which phenocopies ARPKD. We supported this hypothesis by demonstrating: (i) increased content of biologically active split C3 fragments in kidneys from ARPKD and its orthologous model;(ii) presence of C3 mRNA and protein in renal cystic and pericystic cells;and (iii) strong association between renal C3 expression and pace of renal cystogenesis that we validated in crosses of C3 deficient (C3-/-) mice with Cys1cpk/+ mice. In addition, cystogenesis is attenuated in Pkhd1pck rats'introgressed to a strain with low C3 expression. 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 autosomal dominant PKD by reducing the proliferation of cystic tubules. CR3 may also induce pro-cystogenic TNF release and directly activate c-Src in renal tubule cells. Consistent with essential and novel effects of local complement factor production, the capacity of renal tubule cells to produce and activate C3 and dysregulation of this process by a cystogenic defect, we suggest that the C3 effects in ARPKD increase as cystic tubules dilate, forming a vicious cystogenic cycle. Specifically, we hypothesize that C3 pathway activation accelerates cyst formation in ARPKD through a CR3 dependent process. We address this hypothesis in three inter-related aims: 1) Dissect mechanisms underlying cystogenic effects of C3;2) Determine whether C3 production by Pkhd1-expressing cells modulates ARPKD pathogenesis;and 3) Determine the role of complement component receptor CR3 (or Mac1) in renal 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 these aims will: (i) allo integration of existing knowledge by linking established and novel cystogenic pathways to the C3-CR3 nexus, and (ii) provide a new direction in ARPKD research that may lead to development of novel prognostic and therapeutic strategies.

Public Health Relevance

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 ARPKD progression. Therefore, we propose to establish key relationships of C3 effects in the pathogenesis of ARPKD and provide foundation for pre-clinical ARPKD studies targeting C3-regulated pathways.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Rasooly, Rebekah S
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Mrug, Michal; Zhou, Juling; Yang, Chaozhe et al. (2015) Genetic and Informatic Analyses Implicate Kif12 as a Candidate Gene within the Mpkd2 Locus That Modulates Renal Cystic Disease Severity in the Cys1cpk Mouse. PLoS One 10:e0135678
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