Hypoxia and fibrosis in chronic kidney disease: crossing at pericytes

Abstract

Chronic kidney disease (CKD) is placing an increasing burden on patients and societies because no decisive therapy has been established. Tubulointerstitial lesions accompanied by fibrosis, inflammatory cells, and capillary rarefaction not only characterize, but also aggravate renal dysfunction in CKD. In this setting, renal cells, particularly tubular cells, suffer from hypoxia caused by the imbalance of blood perfusion and oxygen demand despite their adaptive responses represented by upregulation of hypoxia-inducible factors (HIFs). Fibrosis is a pathological state characterized by excess extracellular matrix (ECM) deposition, which is also a hallmark and causative factor of many chronic diseases including CKD. Recent studies have suggested that the dominant origin of ECM-producing myofibroblasts (MFs) may be pericytes, which are indispensable cells for maintaining proper capillary functions, as they wrap capillaries and stabilize them through a fine-tuned interplay with endothelial cells. During fibrosis, pericytes are activated and detach from capillaries before conversion into MFs, which compromises capillaries and worsens hypoxia. We also discuss how hypoxia and HIFs affect fibrogenesis. Given that hypoxia is caused by insufficient angiogenesis and that fibrosis results from pericyte loss, restoration of pericytes should be an intriguing target for overcoming both hypoxia and fibrosis. We propose the deactivation of MFs to recover lost pericytes as a promising therapy for CKD.

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

“…97,98 Hypoxia is a recognized final common pathway for the progression of CKD (see below). 99,100 In addition, increase in permeability …”

“…Furthermore, loss of interstitial microvascular and capillary rarefaction may reduce blood supply to regions of the kidney. 99,192 As part of the normal physiological response to hypoxia, cells undergo adaptations in gene expression in order to try to counteract the effect of low oxygen. This response typically involves stimulation of hypoxia indicible factors (HIF)-1 and HIF-2.…”

The cytoskeleton as a novel target for treatment of renal fibrosis

“…Much work has focused on the ability of TGF-1 to induce EMT and SMA expression (Iwano, 2010). However, growth factor signaling, including hepatocyte growth factor, connective tissue growth factor (CTGF) and vascular endothelial growth factor (Nguyen and Golschmeding, 2008;Liu and Yang, 2006;Kang and Johnson, 2003), angiotensin II (Macconi et al, 2014), inflammation (Cao et al, 2015), hypoxia (Kawakami et al, 2014), and the wnt pathway (Tan et al, 2014) are linked to the initiation and progression of renal fibrosis. Despite much research defining these molecular and cellular pathways, translation of these findings to the clinical has yet to impact management of CKD, which still primarily relies on slowing disease progression through managing hypertension and/or diabetes, and minimizing cardiovascular comorbidities (Vassalotti et al, 2016;Roche-Recinos et al, 2015;Townsend and Taler, 2015;Wouters et al, 2015).…”

All-Trans Retinoic Acid Attenuates Hypoxia-Induced Injury in NRK52E Cells via Inhibiting NF-κB/VEGF and TGF-β2/VEGF Pathway

“…Hypoxia has recently been proposed as one of the most important factors in progressive renal injury [1]. By simulating proinflammatory cytokines, hypoxia increases extracellular matrix and decreases turnover in renal fibroblasts, which are key events leading to tubulointerstitial fibrosis and may further impair oxygen diffusion and aggravate regional hypoxia.…”