Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis

Abstract

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signalling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1β. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy.

Keywords: NLRP3 inflammasome; acute kidney injury; haem; pigment nephropathy; rhabdomyolysis.

Figure 1

The canonical inflammasome activation signalling cascade is initiated by signal 1 PAMPs and DAMPs. (a) Signal 1 elicits the activation of PRRs on the cell surface (i). The activation of PRRs results in a downstream signalling cascade, triggering the translocation of NF-κB into the nucleus (ii), where NF-κB upregulates the expression of NLRP3, pro-GSDMD, pro-IL-1β and pro-IL-18 (iii). (b) Signal 2 is provided by an array of PAMPs, DAMPs and HAMPs (iv), including arrested phagocytosis, perturbed membrane potential (ΔΨ_m), endoplasmic reticulum stress, extracellular ATP, and mitochondrial dysfunction. NLPR3 proteins which have co-localized to the mitochondria (v) are ideally located to rapidly respond to these markers of cellular stress. NLRP3 then oligomerizes with ASC and pro-Caspase-1, forming the NLRP3 inflammasome complex (vi). Caspase-1 undergoes self-cleavage whilst bound to the inflammasome complex (vi), driving the post-translational processing of IL-1β, IL-18 and GSDMD. Once cleaved, GSDMD proteins self-oligomerize to form pores in the cell membrane (vii), allowing for the rapid release of IL-1β and IL-18. In addition, these GSDMD pores may also drive cell-death via pyroptosis. ASC: Apoptosis-associated Speck-like protein containing a Caspase-activation-and-recruitment domain; PRR: pattern recognition receptor; PAMP: pathogen-associated molecular pattern; DAMP: damage-associated molecular pattern; nuclear factor kappa-light-chain-enhancer of activated B cells: NF-κB; NLRP3: nucleotide-binding domain-like receptor protein 3; IL: interleukin; GSDMD: Gasdermin D; ROS: reactive oxygen species; ΔΨ_m: mitochondrial membrane potential.

Figure 2

Haem catabolism by HO-1 produces equimolar amounts of carbon monoxide, Biliverdin and labile iron. Biliverdin is converted to bilirubin by biliverdin reductase. Labile Fe can produce ROS, but is rapidly bound to ferritin. Ferritin (PBD ID: 5Z8U) image generated using the RCSB PDB NGL viewer [67]. BVR: Bilirubin reductase; HO-1: Haem oxygenase-1.

Figure 3

Potential pathways underlying haem-associated kidney injury. Free haem generated by rhabdomyolysis and haemolysis are effectively removed by HO-1 and hemopexin. The binding capacity of these proteins is saturated in pathological conditions and free haem continues to be present. Haemoglobin, myoglobin and plasma free-haem are freely filtered by the glomerulus and can be deposited within the tubules. Oxidative stress, renal vasoconstriction, tubular obstruction by casts, iron-mediated tubular toxicity and inflammation play an important role in acute pigment nephropathy. Myoglobin (PBD ID: 1MBN) and haemoglobin (PBD ID: 1BIJ) structures generated using the RCSB PDB NGL viewer [67]. NLRP3: nucleotide-binding domain-like receptor protein 3; HO-1: Haem Oxygenase-1; ROS: Reactive Oxygen Species.