Inflammation and Fibrosis in Polycystic Kidney Disease

Abstract

Polycystic kidney disease (PKD) is a commonly inherited disorder characterized by cyst formation and fibrosis (Wilson, N Engl J Med 350:151-164, 2004) and is caused by mutations in cilia or cilia-related proteins, such as polycystin 1 or 2 (Oh and Katsanis, Development 139:443-448, 2012; Kotsis et al., Nephrol Dial Transplant 28:518-526, 2013). A major pathological feature of PKD is the development of interstitial inflammation and fibrosis with an associated accumulation of inflammatory cells (Grantham, N Engl J Med 359:1477-1485, 2008; Zeier et al., Kidney Int 42:1259-1265, 1992; Ibrahim, Sci World J 7:1757-1767, 2007). It is unclear whether inflammation is a driving force for cyst formation or a consequence of the pathology (Ta et al., Nephrology 18:317-330, 2013) as in some murine models cysts are present prior to the increase in inflammatory cells (Phillips et al., Kidney Blood Press Res 30:129-144, 2007; Takahashi et al., J Am Soc Nephrol JASN 1:980-989, 1991), while in other models the increase in inflammatory cells is present prior to or coincident with cyst initiation (Cowley et al., Kidney Int 43:522-534, 1993, Kidney Int 60:2087-2096, 2001). Additional support for inflammation as an important contributor to cystic kidney disease is the increased expression of many pro-inflammatory cytokines in murine models and human patients with cystic kidney disease (Karihaloo et al., J Am Soc Nephrol JASN 22:1809-1814, 2011; Swenson-Fields et al., Kidney Int, 2013; Li et al., Nat Med 14:863-868, 2008a). Based on these data, an emerging model in the field is that disruption of primary cilia on tubule epithelial cells leads to abnormal cytokine cross talk between the epithelium and the inflammatory cells contributing to cyst growth and fibrosis (Ta et al., Nephrology 18:317-330, 2013). These cytokines are produced by interstitial fibroblasts, inflammatory cells, and tubule epithelial cells and activate multiple pathways including the JAK-STAT and NF-κB signaling (Qin et al., J Am Soc Nephrol JASN 23:1309-1318, 2012; Park et al., Am J Nephrol 32:169-178, 2010; Bhunia et al., Cell 109:157-168, 2002). Indeed, inflammatory cells are responsible for producing several of the pro-fibrotic growth factors observed in PKD patients with fibrosis (Nakamura et al., Am J Nephrol 20:32-36, 2000; Wilson et al., J Cell Physiol 150:360-369, 1992; Song et al., Hum Mol Genet 18:2328-2343, 2009; Schieren et al., Nephrol Dial Transplant 21:1816-1824, 2006). These growth factors trigger epithelial cell proliferation and myofibroblast activation that stimulate the production of extracellular matrix (ECM) genes including collagen types 1 and 3 and fibronectin, leading to reduced glomerular function with approximately 50% of ADPKD patients progressing to end-stage renal disease (ESRD). Therefore, treatments designed to reduce inflammation and slow the rate of fibrosis are becoming important targets that hold promise to improve patient life span and quality of life. In fact, recent studies in several PKD mouse models indicate that depletion of macrophages reduces cyst severity. In this chapter, we review the potential mechanisms of interstitial inflammation in PKD with a focus on ADPKD and discuss the role of interstitial inflammation in progression to fibrosis and ESRD.

Fig. 12.1

Proposed model focused on the involvement of macrophages following renal injury under normal conditions and in the presence of ciliary or polycystin dysfunction. (a) During steady state, primary cilia protrude into the lumen of renal tubules. Macrophages (M2 like) are present in the interstitial space surrounding the renal tubules. (b) Following injury, there is increased accumulation of macrophage populations (M1-like) or (M2-like) in the interstitial space of the kidney. Furthermore, cilia length initially increases following injury followed by cilia regression during stages of rapid epithelial cell proliferation. (c) During the repair phase in the normal mouse kidney, the injured tubules proliferate, downregulate inflammatory cell accumulation, reform primary cilia, and fully repair the injured epithelium. (d) However, in the cilia or PKD mutant mouse kidney, there is an increased accumulation of macrophage populations (M1 and M2) which fail to properly resolve following injury. The persistent increase in macrophage number leads to enhanced secretion of pro-inflammatory and pro-fibrotic cytokines which causes transition of fibroblasts to a myofibroblast phenotype. These myofibroblasts produce large amounts of extracellular matrix proteins leading to deposition of collagen into the extracellular matrix and fibrosis in the PKD kidney

Fig. 12.2

Inflammatory signaling pathways activated under normal or injured conditions in control, cilia, or PKD mutant epithelial cells. (a) During homeostasis, NF-κB and JAK-STAT signaling pathways are not activated. (b) In injured wild-type epithelial cells, PC1 undergoes C-terminal tail (CTT) proteolytic cleavage. The CTT of PC1 translocates into the nucleus where it serves as a co-activator of the STAT signaling pathway. The NF-κB pathway is also activated through ligands, such as TNF-α, binding to their cognate receptors on the cell surface. Collectively, activation of the NF-κB and JAK-STAT signaling pathways induces transient activation of pro-inflammatory genes such as MCP-1, TNF-α, and CSF-1. These cytokines rapidly recruit macrophages to the site of injury leading to production of pro-inflammatory (IL-1β, TNF-α, iNOS) and anti-inflammatory cytokines (IL-10, Wnt7b) that feed back to the injured epithelium leading to tissue repair. (c) In injured PKD or cilia mutant epithelial cells, there is persistently increased NF-κB and JAK-STAT pathway activation. The persistent activation of NF-κB and JAK-STAT signaling leads to enhanced production of pro-inflammatory, pro-fibrotic, and chemoattractant cytokines and increased macrophage accumulation. Accumulated macrophages produce cystogenic cytokines such as TNF-α or Wnt7b that may be responsible for driving cyst formation