Part One The Role Of Heme Oxygenase-1 As An Immunomodulator in Kidney Disease

Abstract

The protein heme oxygenase (HO)-1 has been implicated in the regulations of multiple immunological processes. It is well known that kidney injury is affected by immune mechanisms and that various kidney-disease forms may be a result of autoimmune disease. The current study describes in detail the role of HO-1 in kidney disease and provides the most recent observations of the effect of HO-1 on immune pathways and responses both in animal models of immune-mediated disease forms and inpatient studies.

Keywords

heme oxygenase; kidney; immune injury.

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Introduction Heme oxygenase (HO)-1 has been linked to the regulations of immunological and pathophysiological processes, such as inflammation, apoptosis, and cytoprotection, mainly through its downstream effector molecules, carbon monoxide, bilirubin, and biliverdin. Inflammation and autoimmune diseases are key factors for kidney disease. In the kidney, glomerular capillaries may become targets of inflammation, ultimately leading to severe and irreversible tissue injury. The involvement of HO-1 in immune-mediated forms of kidney injury has been studied extensively. The current study describes in detail the potential role of HO-1, in various forms of kidney injury, as a mediator of immunological mechanisms that drive disease manifestation and progression.

The various forms of kidney injury usually occur due to injury of the renal glomerulus. Due to their highly specialized structure and function, renal glomeruli are known to be particularly vulnerable to injury. Briefly, the glomerulus (Figure 1) is a tri-cellular structure surrounded by the glomerular (Bowman’s) capsule. Endothelial cells line the luminal side of the glomerular basement membrane (GBM); epithelial cells, also known as podocytes, are anchored on the outer surface of the GBM; and mesangial cells support the capillary loops. Glomeruli form a complex microvascular bed, the glomerular tuft, that functions as a highly selective plasma filter while retaining high-molecular-weight molecules and cells in circulation (Figure 1).

HO-1 and IgA Nephropathy

IgA nephropathy is a form of chronic glomerulonephritis characterized by the deposition of IgA immune complexes in glomeruli. It is the most common form of glomerulonephritis worldwide (1]. The majority of cases are idiopathic, but in recent years, secondary forms of the disease have appeared after various infections (Haemophilus para in. influenza, HIV cytomegalovirus)[2].

Symptoms include the onset of macroscopic hematuria usually one or two days after an afebrile infectious episode, thus mimicking infectious glomerulonephritis. Urine analysis of patients with lgA has detected the presence of deformed red blood cells and sometimes red blood cell casts. Mild proteinuria (<1 g/day) is also typical and may occur without hematuria, while serum creatinine levels are usually normal at diagnosis [3].

The pathogenic mechanism that causes IgA nephropathy remains unknown, but accumulated evidence has led to the "four-hit hypothesis", starting with an abnormal glycosylation pattern of IgA (galactose-deficient IgA1) manifested through increased levels of poorly O-galactosylated lgA1 (gd-lgA1) in blood circulation, which causes the production of circulating auto-antibodies and consequentially the formation and deposition of immune complexes in the mesangium [4,5].

IgA nephropathy diagnosis is confirmed with a renal biopsy and immunofluorescence methodology, which reveal granular IgA and complement factor 3 (C3) deposits located in the mesangium with foci of proliferative or necrotic segmental lesions. However, mesangiallgA deposits are considered non-specific and may be detected in many other disorders such as immunoglobulin A-related vasculitis, HIV infection, psoriasis, lung cancer, and several other disorders of the connective tissue. Examination of kidney tissue sections obtained from IgA patients, under an electron microscope showed increased cellularity and an increased matrix in the mesangium, the endocapillary proliferation of neutrophils, and subendothelial deposits. Finally, normal levels of complement factors are detected with immunoassays, while an elevated lgA plasma concentration may sometimes be detected with serum electrophoresis (6].

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Nitric oxide (NO) and advanced oxidation protein products (AOPP) are strong markers of oxidative stress, and their elevated concentrations have been determined in serum samples of patients with severe IgA glomerulopathy [7]. Nakamura et al. compared patients who suffered from IgA nephritis with healthy controls, revealing that exposure to oxidative stress in IgA was of detrimental importance to the progression of renal injury [8]. This could be due to the under-expression of superoxide dismutase (SOD) and the consequent exacerbation of tissue injury due to the suppression of reactive oxygen species (ROS) scavenging ability (10). Furthermore, studies have identified a dinucleotide guanosine thymine (GT) repeat polymorphism of the HO-1 gene promoter that results in increased HO-1 expression when the GT length is shorter (S-allele) rather than when it is longer (L-allele). These two different alleles may influence the onsets and progressions of many different renal diseases [9], and several studies have shown a direct association between short (GT)n repeats and a higher induction rate of HO-1, which promotes the progression of IgA nephropathy [10].

Following intravascular hemolysis, free heme, the natural substrate of HO-1 and a powerful activator of the complement cascade, is released. Heme has been reported to activate the alternative complement pathway [11] and may therefore be implicated in complement-mediated renal injury [12]. Free heme influences innate immune responses through the activation of Toll-like receptor 4 and ROS-dependent pathways, which in turn, through complex signaling pathways, promote the expression of proinflammatory cytokines. In addition, heme degradation byproducts (CO, biliverdin, bilirubin) and HO-1 constitute key molecules that upregulate the secretion of anti-inflammatory cytokines, such as IL-10 [13] (Figure 2). On the other hand, many pro-inflammatory enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), are hemoproteins whose functions may be impaired due to insufficient free heme once that heme has been catalyzed by HO-1 [14]. Micro and/or macroscopic hematuria is a typical symptom of IgA nephropathy that suggests potential induction of HO-1 in the glomeruli [15]. A previous study used various concentrations of hemin to induce glomerular HO-1 expression in vitro and reported that when the concentration of hemin reached a critical level of 200 µM, HO-1 expression started to diminish. This could partly be explained by the fact that various forms of glomerular disease display increased levels of free radicals (OH−), hydrogen peroxide (H2O2), and active Fe²⁺. These may be further augmented by the heme degradation of HO; therefore, an HO-1 expression-limiting mechanism may be necessary [16].

The clinical course of IgAN is highly variable. In many cases, the disease goes unnoticed and requires no treatment. The most important parameters that influence disease progression include the degree of proteinuria, uncontrollable hypertension, and histopathological lesions on biopsies [17].

Patient assessment is usually performed with the “IgA Nephropathy Prediction Tool” (IIgAN-PT) that uses parameters such as histological findings, eGFR, the degree of proteinuria, the blood pressure value, medication before biopsy, and demographics (sex, age, ethnicity) to estimate the individual five-year risk of renal progression toward end-stage renal disease (ESRD). Independently of IIgAN-PT results, all patients should receive supportive hypertension and proteinuria treatment. Supportive therapy consists of medications that inhibit the renin–angiotensin axon, such as angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEi) [18]. These reduce both systemic and intraglomerular blood pressure—and thus glomerular injury due to hypertension—and lower the degree of proteinuria. If a patient’s eGFR is greater than 30 mL/min/1.73 m², the addition of sodium–glucose co-transporter 2 (SGLT2) to their therapy could further reduce proteinuria [19]. Finally, due to toxicity effects, the use of steroids is only supported in cases of rapid declines in renal function and uncontrolled increases in proteinuria [20].

HO-1 and Membranous Nephropathy (MN)

MN is an autoimmune glomerular disease and a major cause of nephrotic syndrome in the adult population. Symptoms include insidious onset of edema, prominent proteinuria with mild urinary sediment, normal or deteriorating renal function, and normal or elevated blood pressure 21]. Spontaneous remission can be seen in about 30% of patients. In most cases (about 70%), MN is reported as idiopathic. In these cases, antibodies against the M-type phospholipase A2 receptor (PLA2R) found in podocytes are linked to that specific locus and form immune complexes in situ that activate the complement membrane attack complex (MAC, C5b-9). However, MN can also develop as secondary MN due to a specific etiological factor. The main causes are solid tumors (lung, colon, rectum, kidney, breast stomach), autoimmune diseases, and microbial infections. In fact, in areas that are endemic to infections, such as malaria or schistosomiasis, the latter will consist of the main cause of MN [21].

The diagnosis of MN is also based on renal biopsy. Optical microscopy reveals the diffuse thickening of the GBM as a reaction to the subepithelial formation of immune complexes. No cellular hyperplasia or inflammatory cells are detected. The glomerular basement membrane thickens homogeneously but gradually creates protrusions into the subepithelial space that eventually embraces and integrates the immune complexes into it. Immunofluorescence detects granular deposits of lgG and C3 along the basement mem. brane, while electron microscopy uncovers diffuse effacement of podocyte foot processes as well as dense deposits in the subepithelial area (21]. Heymann et. al. described for the first time an experimental rat model of MN in which the pathogenic role of immune complexes was confirmed (22]. Heymann nephritis(HN) was induced through injections of proximal tubule brush border antigens (active HN)or their corresponding antibodies (passive HN) into rats. The autoantigen target in HNis megalin, a transmembrane protein located in the brush border of the proximal tubule and on podocyte foot processes in rats (23]. Studies of active and passive HN proved that subepithelial deposits are formed in situ against a constitutional endogenous antigen rather than through a circulating immune complex 24). The HN model has allowed researchers to identify the important role of complement-mediated cytotoxicity in podocyte injury and proteinuria in this model. Early studies in HN showed co-localization of C3 and C5b-9 to the immune deposits. Furthermore, it was shown that the podocytes that were present in the urine of passive HN rats were coated with C5b-9 [25]. HN progression correlated with persisting urinary excretion of C5b-9, indicating continuous complement activation at the GBM.

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Membrane-bound proteins, known as complement regulatory proteins (CRPs), act to eliminate complement activation and therefore MAC formation and lysis. A well-known CRP is the decay-accelerating factor (DAF, CD55). The DAF accelerates the decay of C3 and C5 convertases and thus restricts MAC formation [26]. In rats, other CRPs are Crry and CD59 [26]. Studies of DAF expression in rats have revealed constitutive DAF expression exclusively in podocytes [27]. To study the protective role of the DAF in complement-induced podocyte injury, a previous study generated a transgenic rat model of DAF depletion (Daf −/−) [28]. Histological, clinical, and biochemical examinations (creatinine levels, albuminuria, urine albumin to urine creatinine ratio) in Daf +/+ and Daf −/− rats demonstrated no significant differences before administration of complement-fixing antibody anti-Fx1A. Following anti-Fx1A administration, proteinuria levels were significantly elevated in Daf −/− rats. Immunofluorescence staining in rats that received anti-Fx1A evidenced greater C3 depositions in Daf −/− rats than in Daf +/+ rats, suggesting a protective role of the DAF in podocyte complement-induced injury [28]. Several studies have demonstrated that HO-1 upregulates the DAF, which in turn reduces complement activation and complement-mediated injury [16]. In that context, HO-1 induction could be a useful tool as a potential treatment strategy against complement-mediated glomerulonephritis via its immunomodulatory effects, including DAF induction.

To explore the previously mentioned properties of HO-1, Wu et al. used an experimental animal model of induced MN in BALB/c mice by introducing intravenously cationic bovine serum albumin and dividing the animals into three groups. The first group was treated with a weekly intraperitoneal administration of cobalt protoporphyrin (CoPP), an HO-1 inducer; the second with tin protoporphyrin (SnPP), an HO-1 inhibitor; and the third with saline. The MN-CoPP group exhibited an HO-1 upregulation and presented a clear improvement of symptoms (a decrease in proteinuria and normalization of the serum albumin and cholesterol levels). CoPP treatment also significantly reduced the production of serum anti-cBSA antibodies. Although immunofluorescence staining remained positive for all three groups, the MN-CoPP group exhibited lesser intensity in the glomerular membrane and reduced C3 depositions concerning the other two groups, especially the MN-SnPP group. The concentrations of markers of oxidative stress, such as thiobarbituric acid reactive substances (TBARSs), were evaluated both in the serum and the kidneys and found to be notably higher concerning non-MN mice, but significant differences were assessed between the MN-CoPP group and the MN-SnPP group. CoPP treatment decreased oxidative stress markers both in the serum and the kidneys, suggesting that HO-1 may have an antioxidative effect on a local and systemic level [29].

Complement activation seems to induce ROS in podocytes that undergo mitochondrial dysregulation in MN [24]. Pyroptosis is a recently identified type of regulated cell death that follows bacterial or viral infections (40). Complex signaling pathways, including activation of inflammasomes and pro-inflammatory cytokines, lead to activation of caspase-1 and consequently formation of pores on the membranes, resulting in cell death and excess of pro-inflammatory cytokines and ROS [30]. Wang et al. described complement-mediated pyroptosis in podocytes with concurrent mitochondrial depolarization and ROS production. Blocking ROS production reversed complement-mediated pyroptosis. Immunohistochemistry of MN glomeruli confirmed the co-localization of pyroptosis-related proteins, such as caspase-1 and gastrin D (GSDMD), as well as synaptopodin, an actin-associated protein found in podocytes. Furthermore, C3a and C5a promoted overexpression of caspase-1 and GSDMD in the podocytes in vitro and influenced the integrity of cellular membranes and the depolarization of the podocyte mitochondrial membranes. When the podocytes of MN patients were incubated with inhibitors of key pyroptosis molecules, C3a and C5a did not affect podocyte membrane integrity [31].

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Recent studies have assessed the role of HO-1 in blocking pyroptosis. Carbon monoxide (CO) as a byproduct of the HO-1 catalysis of hemin seems to block activation of caspase-1 through direct inhibition of its inducer molecule, NLRP3-ASC [32,33]. The NFE2-related factor (Nrf2) is a transcriptional factor that regulates the cellular antioxidant response to oxidative stress by inducing the expressions of antioxidant and cytoprotective molecules, one of which is HO-1 [34]. Sirtuin is a deacetylase protein essential to the integrity of podocytes’ cytoskeletons [35]. Under stress conditions, sirtuin seems to induce overexpression of Nrf2 which leads to upregulation of HO-1 expression in podocytes [36]. In a murine renal ischemia/reperfusion (I/R) injury model, Diao et al. investigated the role of the NF-E2-related factor/heme oxygenase-1 (Nrf2/HO-1) as a protective factor against pyroptosis [37]. Protein arginine methylation transferase 5 (PRMT5) is involved in a vast number of physiological and pathological conditions, among them embryonic development, tissue homeostasis, and malignancies [38]. PRMT5 is implicated in I/R-induced ROS production. Its inhibition resulted in an upregulation of Nrf2/HO-1, a reduction of oxidative stress markers, and a decrease in tissue injury [37].

The highly variable course of MN renders its personalized treatment essential according to the risk of renal impairment progression. Spontaneous remission may occur in about 30% of patients; however, all patients presented with proteinuria should be treated either with an angiotensin receptor blocker (ARB) or an ACEi for three to six months. According to the latest MN treatment guidelines, all patients should be assessed for anti-M-type phospholipase A2 receptor (PLA2R) antibody levels in the blood before and during treatment, as an absence of anti-PLA2R antibodies in a patient with an initial positive test indicates remission. Corticosteroids plus cyclophosphamide administration, along with supportive therapy, are recommended for patients with severe nephrotic syndrome and a rapid decline of renal function at the onset of the disease [39]. In moderate- to high-risk patients, if remission is not achieved within six months of supportive therapy alone, immunosuppressive treatment with rituximab, calcineurin inhibitors (CNIs) and corticosteroids plus cyclophosphamide may be used unless contraindicated due to severe renal impairment, diffuse interstitial fibrosis or recurrent infections [18].

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Virginia Athanassiadou 1 , Stella Plavoukou 1 , Eirini Grapsa 1 and Maria G. Detsika 2,

1. Department of Nephrology, School of Medicine, National and Kapodistrian University of Athens, Aretaieion University Hospital, 11528 Athens, Greece

2. 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos, and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece