Progression of Tubulointerstitial Fibrosis and the Chronic Kidney Disease Phenotype - Role of Risk Factors and Epigenetics

Abstract

Although the kidney has capacity to repair after mild injury, ongoing or severe damage results in scarring (fibrosis) and an associated progressive loss of kidney function. However, despite its universal significance, evidence highlights a population based heterogeneity in the trajectory of chronic kidney disease (CKD) in these patients. To explain the heterogeneity of the CKD phenotype requires an understanding of the relevant risk factors for fibrosis. These factors include both the extrinsic nature of injury, and intrinsic factors such as age, gender, genetics, and perpetual activation of fibroblasts through priming. In many cases an additional level of regulation is provided by epigenetic mechanisms which integrate the various pro-fibrotic and anti-fibrotic triggers in fibrogenesis. In this review we therefore examine the various molecular and structural changes of fibrosis, and how they are influenced by extrinsic and intrinsic factors. Our aim is to provide a unifying hypothesis to help explain the transition from acute to CKD.

Keywords: TGF-β1; autocrine; epigenetics; fibrogenesis; fibrosis; kidney disease.

FIGURE 1

Determinants of the chronic kidney disease (CKD) phenotype. Schematic representation of the interplay of extrinsic and intrinsic risk factors in the progression of CKD, and their effects on myofibroblast differentiation. Fibroblast recruitment and activation is under control of paracrine and autocrine signals released in response to injury. The schema highlights the significance of an autocrine amplification of transforming growth factor beta1 (TGF-β1) signaling in injury-primed cells and their perpetual activation through epigenetic mechanisms. TGF-β1 is secreted as an inactive dimeric complex with latency associated peptide (LAP), bound in turn to latent TGF-β binding protein (LTBP). These complexes are subsequently incorporated into the extracellular matrix (ECM) and must be cleaved to release active TGF-β1. TGF-β binding proteins (TBPs) abundant in the extracellular fluid (e.g., decorin, betaglycan, fucoidan, heparin) also sequester TGF-β1, limiting activation at remote sites. Structurally, diffusion of TGF-β1 is also restricted by tubule basement membranes (not shown). Activation is therefore constrained to the fibroblast cell surface, where multi-step proteolysis releases TGF-β1 and allows binding to its cognate receptor complex (TGFBR) in an exclusively autocrine fashion. Canonical signaling via Smad phosphorylation drives the expression of intracellular α-smooth muscle actin expression (Acta2), ECM synthesis and further TGF-β1 gene expression generating an autoinductive feed-forward loop.

FIGURE 2

Inherent similarities between fibrosis in different species and organs. Silver–Masson trichrome staining of a diabetic (A) human and (B) rat kidney showing the underlying similarity of fibrosis in the two organs. Immunohistochemical staining for αSMA (brown) showing myofibroblast recruitment in the rat after(C) bile duct ligation in the liver and (D) unilateral ureteric ligation in the kidney. Scale bar = 100 μm. [Derived with modification from Hewitson (2012)].