Is the proximal tubule the focus of tubulointerstitial fibrosis?

Abstract

Tubulointerstitial fibrosis (TIF), a common end result of almost all progressive chronic kidney diseases (CKD), is also the best predictor of kidney survival. Almost all cells in the kidney are involved in the progression of TIF. Myofibroblasts, the primary producers of extracellular matrix, have previously received a great deal of attention; however, a large body of emerging evidence reveals that proximal tubule (PT) plays a central role in TIF progression. In response to injury, renal tubular epithelial cells (TECs) transform into inflammatory and fibroblastic cells, producing various bioactive molecules that drive interstitial inflammation and fibrosis. Here we reviewed the increasing evidence for the key role of the PT in promoting TIF in tubulointerstitial and glomerular injury and discussed the therapeutic targets and carrier systems involving the PT that holds particular promise for treating patients with fibrotic nephropathy.

Keywords: Chronic kidney disease; Extracellular matrix; Proximal tubule; Tubulointerstitial fibrosis.

Fig. 1

Major events in renal fibrosis. Inflammation is activated as the initiating event when the kidney is subjected to injury. Inflammatory cells, including T-lymphocytes, macrophages, and dendritic cells, infiltrate the peritubular region resulting in the production of molecules such as ROS that damage the tissue and induce the production of fibrotic cytokines and growth factors. The inflammatory microenvironment that develops after renal injury activates fibroblasts, TECs, endothelial cells, podocytes, pericytes, mesangial cells and macrophages converting into myofibroblasts to produce matrix. Depending on the severity and duration of injury, renal tubular cells exhibit a wide range of responses, such as proliferation, activated unfolded protein response (UPR), autophagy, senescence, G2/M arrest, apoptosis and EMT. There is a lot of controversy on the occurrence and subsequent effect of EMT. There are currently two views of EMT: complete EMT (absence of epithelial markers, expression of mesenchymal markers, and crossing tubular basement membrane into myofibroblasts) (abbreviated as EMT) and partial EMT (TECs acquire mesenchymal characteristics and are capable of producing a variety of pro-fibrotic factors and cytokines, but remain attached to the basement membrane). Metabolic changes that damage the renal tubules such as decreased FAO and upregulation of glycolysis can promote the process of TIF. The damage also impairs the glomerular structure, as glomerulosclerosis develops as a result of the loss of podocytes, thickening ofGBM, and expansion of the mesangial cells. Glomerulosclerosis and TIF together make up renal fibrosis (pathological changes in the vasculature are not shown in this figure).

Fig. 2

Mechanisms of glomerular injury mediating PT TIF. Local PT extension and increased protein reabsorption are two mechanisms by which glomerular injury cause TIF that are not mutually exclusive, and their arguments can be explained by model differences.

Fig. 3

PT-targeted drugs and delivery systems for the treatment of CKD.