EMMPRIN/CD147
EMMPRIN, currently referred to as CD147 or EMMPRIN/CD147, is a membrane glycoprotein, which was originally discovered in various animal tissues and thus received different names. The name EMMPRIN (extracellular matrix metalloproteinase inducer) was given to its human equivalent, and it has been kept in use in order to underline its significant role in regulating metalloproteinases. It has been proven to stimulate MMP-1, MMP-2 and MMP-3. Its role in acute kidney injury (AKI) secondary to ischemia and in CKD progression has been observed. It is found in the kidney on the basolateral side of tubular epithelial cells. [4]
CD147/AKI
Ischemia-reperfusion injury (IRI) of the renal allograft is the main cause of delayed graft function (DGF). In an experimental study, IRI induced in murine models deprived of the gene coding for CD147 led to a considerable reduction in the infiltration by neutrophils and macrophages and, consequently, a substantial drop in the degree of tubulointerstitial injury than in the models carrying that gene. [5] This experiment proved EMMPRIN’s key role in exacerbating the inflammatory infiltration in this type of injury. By pharmacologically inhibiting CD147, Seizer prevented infiltration by neutrophils and macrophages/monocytes following myocardial infarction. [6] Its proinflammatory activity may be associated with some interaction with cyclophilin A (a ligand of CD147), which plays a crucial role in regulating inflammation. This mechanism has been proven to take place in numerous in vivo experiments in sepsis-induced AKI, bronchial asthma, lipopolysaccharide-induced lung injury and collagen-induced arthritis. [7] There are no reports on CD147 in the context of renal graft IRI, but its role in spreading inflammation can be deduced from the native kidney IRI model. Elevated CD147 concentrations have been shown to be present in acute kidney injury. [8] Moreover, its concentration has been observed to positively correlate with creatinine levels. Serum CD147 originates in soluble CD147 from leukocytes, and urine CD147 is related to tubular injury. Based on clinical research, this compound is believed to be the first candidate for a biomarker allowing for diagnosing AKI.[5,8] The occurrence of DGF is associated with a 2.9-times higher risk of renal allograft failure in the long-term follow-up, hence its importance as a prognostic factor. Also, some authors have reported that DGF increases the incidence of acute kidney rejection episodes. [9] In this study, patients with DGF during the early post-transplantation period had far higher CD147/EMMPRIN concentrations in the late post-transplantation period. This phenomenon could be associated with the activation of CD147 and its maintained increased expression in the kidney transplant in the long-term follow-up. In acute renal reperfusion injury, fibrotic processes due to EMT begin in the kidney, where CD147 plays the major role.
CKD vs EMT
Although there are various clinical causes of chronic kidney disease, progression in each case is associated with the damaging effects of fibrosis. [1] Renal fibrosis is characterized by tubulointerstitial fibrosis, glomerulosclerosis and destruction of renal structure. The main cause of renal fibrosis is found to be the activation and interstitial accumulation of fibroblasts and myofibroblasts surrounded by excessive amounts of extracellular matrix (ECM). Renal myofibroblasts emerge de novo during renal fibrosis and represent the phenotype of fibroblasts that result from differentiation caused by cellular stress. [2] This type of fibroblasts or myofibroblasts come from the so-called residential quiescent tissue fibroblasts and vascular pericytes, or originate in epithelial-to-mesenchymal transition (EMT) and in bone marrow. [3] In EMT, epithelial cells transform into mesenchymal stem cells. They acquire the capability to produce collagen. For EMT to develop fully, the basement membrane to which the epithelial cells adhere must be injured and the cells must migrate to the interstitium. EMT is the fundamental mechanism by which the kidney becomes fibrotic during the CKD process. It is also present in such physiological situations as embryogenesis. In pathological states, its main role consists in causing organ (mostly lung) fibrosis in the course of inflammation, and initiating cancer infiltration and metastasis. [10] The sort of EMT related to inflammation is a type of wound healing and scar formation and is referred to as type 2 EMT. If the inflammation induced by injury persists, fibroblast numbers are up dramatically and the organ’s structure is damaged, which state is referred to as chronic type 2 EMT. [10] As mentioned above, basement membrane damage is one of the main stages of EMT, as it allows the transformed cells to migrate to the interstitium. Matrix metalloproteinase-2 (MMP-2) is the key compound responsible for this phenomenon. [10] Since EMT was first discovered by Elizabeth Hay in 1960, many authors have proven its leading role in renal fibrosis and destruction in animal and human biopsy specimens. [10]
EMT vs CD147/EMMPRIN
It is known that CD147 abundant in the renal tubules is a very strong activator of MMP-2 – the basement membrane-degrading metalloproteinase required for EMT to take place. [11] An in vitro experiment showed that in renal tubular epithelial cells CD147, together with MMP, induces the production of hyaluronic acid, which participates in the differentiation of the tubular epithelial cells into myofibroblasts in response to TGF-β. Hyaluronan promotes the emergence of proteins typical of fibroblasts on the surface of the transforming cells. [12] Similarly to acute kidney injury, CD147’s role in stimulating inflammatory infiltration by macrophages and monocytes in chronic kidney injury has been proven. [13] CD147 is thought to exacerbate fibrosis following three mechanisms: hyaluronan induction, MMP (particularly MMP-2) induction and inflammatory infiltration. Our study showed that the concentration of CD147 correlated negatively with eGFR at the time of sampling – 70 months post Tx on average. The level of CD147 at the end of the follow-up period correlated negatively with eGFR at 1 and 2 years post Tx, as well. These results prove that its high activity is most apparently linked to worse renal graft function since the very beginning – the early post-transplantation period and at 1 and 2 years post Tx. Kemmner et al. came to similar conclusions after they analyzed the presence of CD147 in biopsy specimens collected from renal graft recipients (50 months post Tx on average) in the context of renal graft function and chronic histopathological lesions in the form of IF/TA. They found that abundant CD147 in the biopsy specimen was associated with more pronounced FT/TA lesions, poorer renal graft function evaluated using eGFR values, and an unfavorable change of renal graft function over time. [11] Another researcher, Yoshiko Mori et al., monitored the correlation of urine and plasma CD147 concentrations with renal graft function in patients with different kidney diseases. [14] There is very little information available on EMMPRIN expression in the renal tissue, especially in renal grafts. Most research into this compound is related to cancer and cancer invasion. [15] In many cancers, the effect of EMMPRIN on EMT processes linked to cancer invasion has been proven. [15] EMMPRIN plays a proven role in lung fibrosis secondary to inflammatory diseases. [16] Similarly to Kemmner’s results, in our study EMMPRIN corelated positively with IF/TA histopathological lesions. Interstitial fibrosis (CI) demonstrated 4 degrees of lesion severity (0: ≤ 5%, 1: 6-25%, 2: 26-50%, 3: >50%), similarly to tubular atrophy CT (0: no atrophy, 1: ≤25%, 2: 26-50%, 3: >50%). The more severe interstitial fibrosis and tubular atrophy, the higher CD147 concentration. Corresponding results were obtained by Shiren Sun et al., who studied the severity of IF/TA lesions in renal biopsy specimens collected from IgA nephropathy patients and found that an increased expression of CD147 was associated with more severe chronic lesions. Additionally, CD147 levels correlated positively with creatinine concentrations and negatively with eGFR. [17] One experimental study on murine models established that mice deprived of the gene coding for CD147 had far less fibrotic lesions in the kidneys at 14 days after bilateral ureteral occlusion. Also, no expression of MMP-2, an element of key importance to EMT, was found in the models. [18] CD147 is a strong stimulator of MMP-2, an enzyme that in children persists at increased levels since the beginning of renal injury and during its progression correlates with the concentration of TGF-β, the main stimulator of fibrosis. MMP-2 is believed to be an indicator of exacerbated cellular damage, inflammation and elevated proteolytic processes in children with CKD. [19] The positive correlation between EMMPRIN levels and mesangial matrix expansion (MM) lesions in the glomeruli that was found in our study reflected the effect of CD147 on increased ECM amounts in the glomerular spaces between the mesangial cells. This effect may be exerted by a decreased activity of metalloproteinases. Other histopathological lesions that CD147 correlates with, namely double contours of the GBM (CG) and arteriolar hyalinosis (AH), do not lend themselves to easy interpretation. CG may be present in the picture of many pathologies, such as chronic or chronic active humoral rejection, thrombotic microangiopathy, hypertension-related glomerulopathy and glomerulonephritis. According to BANFF classification criteria from 1997, as updated, (AH) is a lesion of „uncertain significance”. [20] The positive correlation between CD147 levels and urine protein concentrations is an important aspect of our results. Proteinuria is a known marker for kidney diseases. Anti-proteinuria treatment improves the prognosis for renal function. Apart from being a marker, however, proteinuria is also a factor contributing to the progression of renal failure. [21.22,23] By exacerbating kidney injury, CD147 increases proteinuria, which has an additional exacerbating effect on the progression of renal allograft failure. Similar results were obtained by Yoshiko et al., who established a positive correlation between urine CD147 levels and urine protein concentrations. [14]