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

Abstract

Abstract. Chronic kidney disease (CKD) is a long-term condition in which theChronic kidney disease (CKD) represents a serious hazard to human health, and has a high prevalence. In developed countries, it is estimated that more than 10% of adults present some degree of CKD (1). Despite a varied initial evolution, which is related to the diversity of its aetiologies -namely genetics, autoimmune-related infections, environmental factors, diet, and drugs -progressive renal disease frequently results in renal fibrosis and finally in renal failure. The mechanisms implicated in renal fibrosis are still poorly understood, and existing therapies are ineffective or only slightly successful, hence it is essential to understand the pathophysiological mechanisms underlying the usual development of CKD, and to discover and better understand new strategies for treating this disease. In order to study the biopathology of this disease and to evaluate new treatments, animal models are required. The perfect animal model for renal disease research should have human-like renal anatomy, haemodynamics and physiology, as well as enabling the determination of relevant renal, biochemical and haemodynamic parameters. In all probability, no species can consistently meet all these requirements, and the experimental plan and other constraints often determine the choice of animal models for particular research applications. With this in mind, this review aims to describe and analyze animal models of renal fibrosis and suggest new areas of research. Renal Fibrosis: Aetiology and PathophysiologyDiabetes and hypertension are currently the two principal causes of CKD (2), among other causes such as infectious glomerulonephritis, renal vasculitis, ureteral obstruction, genetic alterations, autoimmune diseases (1) and drugs (3, 4). In general, diabetes causes glomerular hypertension by reducing the afferent arteriolar resistance while stimulating the efferent arterioles (2). Thus, elevated glomerular capillary pressure is one of the major factors in progressive renal sclerosis (5). Diabetes and hypertension gradually lead to glomerular expansion, which causes endothelial dysfunction and haemodynamic changes: loss of the glomerular basement membrane electric charge and its thickening, a decreased number of podocytes, foot-process effacement and mesangial distension have been shown to 1

Relaxin‐2 therapy reverses radiation‐induced fibrosis and restores bladder function in mice

“…The ECM provides strength during contractions, high compliance during relaxation, and low pressure storage of urine . Collagen is continuously synthesized and degraded, but locally produced proinflammatory cytokines and other activators can impair this homeostatic balance by transforming fibroblasts to myofibroblasts to drive fibrosis . Transforming growth factor beta‐1 (TGF‐β1) is implicated in the stimulation of membrane‐cytoskeletal structural protein formation and in the synthesis of ECM through multiple signaling pathways .…”

Association of Metformin Use With End‐Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay‐for‐Performance Program

“…The progression from CKD to ESRD is associated with the loss of kidney cells and replacement by the extracellular matrix (ECM) independent of primary underlying disease . An imbalance between excessive synthesis and decreased breakdown of the ECM causes glomerulosclerosis and tubule‐interstitial fibrosis leading to CKD . Numerous in vitro and in vivo studies have indicated that metformin attenuates renal fibrogenesis, mainly by activating activity biomarkers of AMP‐activated protein kinase and target of rapamycin, thus exerting an antiapoptotic effect on podocytes in a high‐glucose environment and reducing the loss of podocytes in DM nephropathy .…”

Curcumin alleviates ischemia reperfusion‐induced late kidney fibrosis through the APPL1/Akt signaling pathway

“…In these etiologies, due to the high clinical rates of renal IR injury, especially in the perioperative period, such as with partial nephrectomy, kidney transplantation, and intraoperative hypotension, AKI has received more attention from scholars. Large amounts of evidence have indicated that IR‐induced AKI could cause laterenal fibrosis (Guo et al, ; Kim & Padanilam, ; Zhou et al, ), a common process for the progression of CKD to end‐stage renal disease (Nogueira, Pires, & Oliveira, ). Collagen I is a heterotrimer composed of two α1 and one α2 collagen peptide that plays an important regulatory role in the process of tissue fibrosis (Wada et al, ).…”