Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

Abstract

Chronic kidney disease (CKD) is a long-term condition in which the kidneys do not work correctly. It has a high prevalence and represents a serious hazard to human health and estimated to affects hundreds of millions of people. Diabetes and hypertension are the two principal causes of CKD. The progression of CKD is characterized by the loss of renal cells and their replacement by extracellular matrix (ECM), independently of the associated disease. Thus, one of the consequences of CKD is glomerulosclerosis and tubulointerstitial fibrosis caused by an imbalance between excessive synthesis and reduced breakdown of the ECM. There are many molecules and cells that are associated with progression of renal fibrosis e.g. angiotensin II (Ang II). Therefore, in order to understand the biopathology of renal fibrosis and for the evaluation of new treatments, the use of animal models is crucial such as: surgical, chemical and physical models, spontaneous models, genetic models and in vitro models. However, there are currently no effective treatments for preventing the progression of renal fibrosis. Therefore it is essential to improve our knowledge of the cellular and molecular mechanisms of the progress of renal fibrosis in order to achieve a reversion/elimination of renal fibrosis.

Keywords: Rats; disease; kidneys; mice; renal function; review.

Figure 1. Glomerular injury can be associated with different causes, leading to endothelial dysfunction and haemodynamic changes. Activation and amplification of many biological effects particularly with production of angiotensin II (Ang II) that up-regulates the expression of other factors, such as transforming growth factor-β (TGFβ), connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI1) and nuclear factor ĸB (NFĸB), leading to initial recruitment of neutrophils which is substituted by macrophages and T-lymphocytes, triggering an immune response, causing interstitial nephritis. Tubular cells respond to this inflammatory process by forming a lesion of the basal membrane and by epithelial–mesenchymal transition transformed into interstitial fibroblasts. The formed fibroblasts produce collagen, and result in an imbalance between excessive synthesis and decreased breakdown of the extracellular matrix, which in turn damages the blood vessels and the kidney tubules, with the possibility of forming of a cellular scar and consequently renal fibrosis. RAAS: Renin–angiotensin–aldosterone system.

Figure 2. Effective and new treatments of renal fibrosis. PDGF: Platelet-derived growth factors; PAI1: plasminogen activator inhibitor-1; CTGF: connective tissue growth factor; DDR1: discoidin domain receptor 1; TGFβ: transforming growth factor-β; NFĸB: nuclear factor-ĸB; NADPH: nicotinamide adenine dinucleotide phosphate; mRNA: messenger ribonucleic acid.