The role of interstitial changes in the progression of chronic kidney disease

Abstract

Interstitium - the renal tubulointerstitial compartment - is located between the renal tubule basement membrane and microcirculation vessels. Interstitial fibroblasts produce the extracellular matrix and constitute the structure's cellular skeleton, regulating spatial relationships between its components (microenvironment). The tubular epithelium and endothelium cooperate within an integrated microenvironment. Structural or functional impairment of the extracellular matrix, microcirculation vessels or tubular epithelium results in disturbances of tubulointerstitial compartment components. In the course of glomerular kidney diseases, the intrarenal RAA system becomes activated and inflammatory mediators are released. Interstitial inflammation and microcirculatory disorders develop, inducing adverse consequences, manifested mainly through the process of hypoxia and inflammation. Inflammation-induced increase in interleukin-1 (TNF-α) expression leads to increased concentrations of VEGF, ICAM-1, angiotensin II, IL-6 and IL-8. Cytokines activate fibroblasts, myofibroblasts and endothelial cells. Fibrosis is also triggered by HIF-1alpha pathway activation, resulting in vascular growth and fibroblast proliferation. This reaction likewise occurs through activation of NF-ĸβ, EPO, GLUT-1, IGF-1 and INOS. Interstitial fibrosis is one of the factors determining the clinical course of kidney diseases. Apart from inducing fibrosis, microcirculatory disorders lead to the progression of hypoxia. Angiogenesis is a part of the repair process accompanying fibrosis. Its determinant is the normal function and structure of endothelial cells manifested by their ability to migrate and proliferate in response to, inter alia, angiopoietins, VEGF and nitric oxide synthase. Administering a three-drug RAAS-inhibiting therapy to patients with chronic glomerulopathies improves tubular function, measured by the decrease in excretion of NAG and propeptide of type III procollagen fibres, and contributes to the improvement in microcirculation functioning.