Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2

Abstract

Despite recent advances in the management of chronic kidney disease (CKD), morbidity and mortality rates in these patients remain high. Although pressure-mediated injury is a well-recognized mechanism of disease progression in CKD, emerging data indicate that an intermediate phenotype involving chronic inflammation, oxidative stress, hypoxia, senescence, and mitochondrial dysfunction plays a key role in the etiology, progression, and pathophysiology of CKD. A variety of factors promote chronic inflammation in CKD, including oxidative stress and the adoption of a proinflammatory phenotype by resident kidney cells. Regulation of proinflammatory and anti-inflammatory factors through NF-κB- and nuclear factor, erythroid 2 like 2 (Nrf2)-mediated gene transcription, respectively, plays a critical role in the glomerular and tubular cell response to kidney injury. Chronic inflammation contributes to the decline in glomerular filtration rate (GFR) in CKD. Whereas the role of chronic inflammation in diabetic kidney disease (DKD) has been well-elucidated, there is now substantial evidence indicating unresolved inflammatory processes lead to fibrosis and eventual end-stage kidney disease (ESKD) in several other diseases, such as Alport syndrome, autosomal-dominant polycystic kidney disease (ADPKD), IgA nephropathy (IgAN), and focal segmental glomerulosclerosis (FSGS). In this review, we aim to clarify the mechanisms of chronic inflammation in the pathophysiology and disease progression across the spectrum of kidney diseases, with a focus on Nrf2.

Keywords: Nrf2; chronic inflammation; chronic kidney disease; mitochondrial dysfunction; oxidative stress; resident kidney cells.

Figure 1

Inflammation and metabolism in CKD progression. Inflammation and metabolism are 2 main pathways leading to CKD progression, with Nrf2 serving as the hub. Reproduced with permission from the American Society of Nephrology, from: Integrative biology identifies shared transcriptional networks in CKD, Martini S et al., Vol 25, Issue 11, copyright 2014; permission conveyed through Copyright Clearance Center, Inc. CKD, chronic kidney disease.

Figure 2

Activation of resident kidney cells contributes to chronic inflammation in CKD. Resident kidney cells proliferate and produce proinflammatory chemokines responsible for perpetuating the cycle of chronic inflammation leading to kidney fibrosis. Adapted by permission from Springer Nature. Nat Rev Immunol. The immune system and kidney disease: basic concepts and clinical implications. Kurts C et al. Copyright 2013. IFN-ɑ, interferon alpha; IL-6, interleukin 6; TNF, tumor necrosis factor.

Figure 3

Mediators of chronic kidney disease. Various inflammatory mediators are involved in the complex processes leading to the loss of kidney function. Adapted with permission from Elsevier. Originally published in Eur J Pharmacol. Vol 820. Lv W et al. Inflammation and renal fibrosis: recent developments on key signaling molecules as potential therapeutic targets. Pages 65 to 76. Copyright 2018, Elsevier. ECM, extracellular matrix; EMT, epithelial-mesenchymal transdifferentiation; GFR, glomerular filtration rate; ROS, reactive oxygen species; TNF, tumor necrosis factor; TGF-β, transforming growth factor beta; TWEAK, TNF-like weak inducer of apoptosis.