How PPAR-alpha mediated inflammation may affect the pathophysiology of chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a major risk factor for death in adults. Inflammation plays a role in the pathogenesis of CKD, but the mechanisms are poorly understood. Peroxisome proliferator-activated receptor alpha (PPAR-α) is a nuclear receptor and one of the three members (PPARα, PPARβ/δ, and PPARγ) of the PPARs that plays an important role in ameliorating pathological processes that accelerate acute and chronic kidney disease. Although other PPARs members are well studied, the role of PPAR-α is not well described and its role in inflammation-mediated chronic disease is not clear. Herein, we review the role of PPAR-α in chronic kidney disease with implications for the immune system.

Keywords: Chronic kidney disease; Immunity; Inflammation; PPAR-α; Peroxisome proliferator-activated receptors.

Fig. 1

Map of PPAR expression sites and their physiological functions. The family of PPARs are comprised of three isoforms (PPAR-α, PPAR-β/δ, and PPAR-γ) that are differentially expressed based on their respective physiological roles, tissue distributions, and ligand specificities. PPAR-α is highly expressed across an array of metabolically active tissues, such as liver, heart, skeletal muscle, and intestinal mucosa (Grygiel-Gó and rniak, 2014a).

Fig. 2

Structure and transactivation of PPARs. A/B, Ligand-independent transactivation domain (AF1), DNA-binding domain (C), co-factor docking domain (D) and the ligand-binding domain with ligand-dependent transactivation domain AF2 (E/F).

Fig. 3

Sodium triggers an inflammatory response in antigen-presenting cells. Hyperosmolar Na ⁺ enters APCs through the ENaC to induce oxidative stress and increase isolevuglandin (IsoLG) production which stimulates T-cell proliferation and proinflammatory cytokine release. High sodium environments have also been shown to increase IL-1β production in DCs to modulate SSBP by enticing T cells to produce IL-17A.

Fig. 4

PPAR-α activation upregulates LncRNA Gm15441. PPAR-α activation leads to the upregulation of the long non-coding RNA gene Gm15441 which subsequently suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, leads to decreased NLRP3 stimulation, caspase-1 cleavage, and IL-1β maturation (Brocker et al., 2020).

Fig. 5

Hypothesized role of Inflammation and Immune Cell Activation in Chronic Kidney Disease.