Abstract
Fibrosis is a process characterized by an excessive accumulation of the extracellular matrix as a response to different types of tissue injuries, which leads to organ dysfunction. The process can be initiated by multiple and different stimuli and pathogenic factors which trigger the cascade of reparation converging in molecular signals responsible of initiating and driving fibrosis. Though fibrosis can play a defensive role, in several circumstances at a certain stage, it can progressively become an uncontrolled irreversible and self-maintained process, named pathological fibrosis. Several systems, molecules and responses involved in the pathogenesis of the pathological fibrosis of chronic kidney disease (CKD) will be discussed in this review, putting special attention on inflammation, renin-angiotensin system (RAS), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, microRNAs (miRs), and the vitamin D hormonal system. All of them are key factors of the core and regulatory pathways which drive fibrosis, having a great negative kidney and cardiac impact in CKD.
Highlights
Sanitaria del Principado de Asturias (ISPA), Retic REDinREN-ISCIII, Universidad de Oviedo, Pathology Department, Fundación Instituto de Investigaciones Sanitarias-Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid (UAM), Retic REDinREN-ISCIII, 28040 Madrid, Spain; Equal contribution as first authors
Serum phosphate and fibroblast growth factor 23 (FGF23), which are elevated in the advances stages of chronic kidney disease (CKD) [78], are able to induce cardiac hypertrophy [79,80], and they play an important role in myocardial fibrosis through the stimulation of β-catenin and the TGF-β pathway [81]
An experimental study has shown that paricalcitol attenuated the cardiac hypertrophy and fibrosis [14], by reducing collagen I, TGF-β1 and increasing MMP1, an interstitial collagenase that degrades type I, II, and III structural collagens, favoring the reduction of collagen [14,171]. These experimental data are partly in agreement with the findings described in the PRIMO (Paricalcitol Capsule Benefits in Renal Failure Induced Cardiac Morbidity) trial performed in CKD stages 3–4 patients [172,173,174], in which despite paricalcitol treatment, failed to reduce left ventricular mass, it showed positive effects on some functional cardiac markers, improving left atrial volume and the diastolic function and reducing cardiovascular hospitalizations
Summary
The renin-angiotensin system (RAS) is recognized for its important function in the control of extracellular fluid volume and arterial pressure [41]. Ang-II is the most active component of the RAS, its known effect in the synthesis of collagen and fibronectin stimulates the Smad signaling pathways by TGF-ß-independent mechanism [52]. By the stimulation of the growth of the cardiomyocytes inducting LVH, which in turns increase the proportion of fibroblasts leading to cardiac fibrosis [76] Part of these mechanisms are shared with renal fibrosis [74], where in addition, PTH enhances connective tissue growth factor (CTGF) expression in proximal tubular cells [77]. Serum phosphate and FGF23, which are elevated in the advances stages of CKD [78], are able to induce cardiac hypertrophy [79,80], and they play an important role in myocardial fibrosis through the stimulation of β-catenin and the TGF-β pathway [81]. As the changes in serum PTH, phosphate, FGF23, and Klotho are tightly interrelated, it is difficult to dissect their individual participations, though PTH, the most studied factor, plays a key role in the fibrotic process
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