Acta Diabetologica

, Volume 49, Issue 2, pp 111–117 | Cite as

Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications

  • Takayuki Fujita
  • Norikazu Ogihara
  • Yumi Kamura
  • Atsushi Satomura
  • Yoshinobu Fuke
  • Chie Shimizu
  • Yuki Wada
  • Koichi Matsumoto
Original Article

Abstract

Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

Keywords

Diabetic nephropathy Proinflammatory cytokine Interleukin 18 High-sensitive CRP Oxidative stress Adipokine 

Introduction

Vascular complications dominate the life span and the quality of life in type 2 diabetes mellitus, and it is important to prevent the development and progression of these complications. Vascular complication consists of macroangiopathy such as cerebral infarction and cardiovascular events and microangiopathy such as nephropathy, retinopathy, and neuropathy. Each of these complications differs in their incidence and the stage of their occurrence during the disease. Atherosclerosis is known to contribute to the establishment of macroangiopathy [1], and arteriolosclerosis has been suggested to play a role in the etiology of microangiopathy [2]. Hyperlipidemia, hypertension, smoking, and social stress are reported as risk factors worsening vascular complications [3, 4, 5, 6]. While proinflammatory cytokines and oxidative stress are considered to influence vascular endothelial dysfunction [7, 8] and renal injury [9, 10], the precise mechanism of injury in each organ remains obscure.

The proinflammatory cytokine interleukin 18 (IL-18) is produced by vascular endothelial cells or activated macrophages and induces interferon-γ (INFγ) production [11]. IL-18 is therefore a marker of inflammation induced by endothelial injury and is a prognostic marker for forthcoming cardiovascular events [12]. In obesity, the activated adipocyte produces adipokine, which induces organ injury and microangiopathy [13, 14]. Oxidative stress promotes conversion of free fatty acid (FFA) to lipid peroxide, leading to abnormalities of renal microcirculation. The liver-type fatty acid binding protein (L-FABP) binds to cytotoxic lipid peroxide, which is excreted in the urine [15], and urinary elevation of L-FABP indicates renal stress resulting in kidney injury [16]. 8-Hydroxy-2-deoxyguanosine (8-OHdG) is excreted in the urine after being produced during the repair of DNA injured by oxygen radicals [17], and urinary elevation of 8-OHdG indicates the existence of oxidative stress [18]. In nephropathy, the activated macrophage infiltrates the glomerulus and produces IL-18 in the course of kidney injury [19]. Therefore, the increase of IL-18 suggests another mechanism of glomerular injury by the infiltrated and activated macrophage in addition to usual endothelial injury. In this respect, to investigate the alteration pattern of these factors will clarify the difference of pathological conditions in each complication.

IL-18 from atheroma plaque plays a role on general vascular endothelial injury through the mild and continuous inflammation reaction. While macrophage infiltrated in the kidney excretes IL-18 and induces the glomerular injury in lupus nephritis and other primary glomerular diseases. So IL-18 may also concern in the development of nephropathy in diabetes mellitus through the effect of macrophage-induced IL-18. In this study, we hypothesize that IL-18 specifically contributes to the progression of nephropathy by directly affecting kidney function in addition to its proinflammatory effect. Serum and urinary levels of proinflammatory cytokines, adipokines, and oxidative stress markers were examined in patients with various levels of severity of the complication and were compared with clinical parameters.

Patients and methods

Forty-eight patients with type 2 diabetes mellitus (men: 36 cases, women: 12 cases) were admitted to this study. The distribution of ages varied from 26 to 80 . To simplify the patients’ backgrounds, patients admitted were limited to those with serum creatinine under 2.0 mg/dl and medicated only by sulfonilureas. Patients’ blood pressures were controlled by angiotensin II receptor blocker 1 (ARB) under 130 mmHg (systolic) and under 80 mmHg (diastolic) at their two most recent hospital visits. Mean levels of blood pressure in each group are shown in Tables 1 and 2. There are no significant differences between each group after using the maximum dose of ARB. Diuretics were used to control further hypertension. On registration, the patients were classified to three groups as “NO”, “MILD”, and “SEVERE” for each condition. In the classification of macroangiopathy, “SEVERE” indicates a history of cerebral infarction or cardiovascular events (n = 15), “MILD” indicates a history of transient ischemic attack of syncope or chest pain (n = 13), and “NO” means no such histories (n = 20). In the classification of nephropathy, “SEVERE” indicates a urinary albumin creatinine ratio (ACR) of over 300 mg/g·Cr (n = 11), “MILD” indicates an ACR of more than 40 mg/g·Cr but less than 300 mg/g·Cr (n = 14), and “NO” indicates an ACR of less than 40 mg/g·Cr (n = 23). Patients are divided with the level of urinary albumin excretion but are not divided with renal function. Urine was collected early in the morning and transported to the hospital the same day. In the classification of retinopathy, “SEVERE” indicates retinal vascular proliferation (n = 8), “MILD” indicates retinal vascular extravasation without proliferation (n = 14), and “NO” indicates no retinal abnormalities (n = 26). In the classification of neuropathy, “SEVERE” indicates a defect of Achilles’ tendon reflex (ATR) (n = 13), “MILD” indicates a weakness of ATR (n = 13), and “NO” indicates no ATR abnormalities (n = 22).
Table 1

Comparison of parameters among the severity of renal involvement

 

NO

MILD

SEVERE

Total

Number of patients

23

14

11

48

SBP (mmHg)

121 ± 8

127 ± 10

121 ± 7

124 ± 12

DBP (mmHg)

77 ± 4

78 ± 3

77 ± 2

78 ± 4

BMI (kg/m2)

27.8 ± 0.5

27.2 ± 0.5

28.0 ± 0.6

27.7 ± 0.3

HbA1c (%)

6.9 ± 0.2

7.0 ± 0.2

7.2 ± 0.4

7.0 ± 0.1

LDL-C (mg/dl)

114 ± 7

118 ± 7

123 ± 9

117 ± 5

ACR (mg/g·Cr)

24 ± 3

98 ± 5

1,221 ± 371**

320 ± 109

FFA (μEq/l)

455 ± 50

500 ± 85

383 ± 77

452 ± 38

Cystatin C (mg/l)

0.77 ± 0.03

0.84 ± 0.05

1.07 ± 0.14**

0.86 ± 0.04

Adiponectin (μg/l)

4.3 ± 0.5

6.1 ± 1.4

3.9 ± 0.4

4.7 ± 0.5

H-CRP (ng/ml)

922 ± 267

691 ± 135

3,111 ± 857**

1,356 ± 270

ASP (μg/dl)

201 ± 23

168 ± 21

201 ± 41

192 ± 15

IL-18 (pg/ml)

343 ± 4

332 ± 4*

349 ± 5**

341 ± 3

8-OHdG (μg/g·Cr)

20.2 ± 3.6

23.3 ± 4.9

33.7 ± 8.2

24.2 ± 3.0

L-FABP (μg/g·Cr)

63.1 ± 5.3

65.0 ± 6.1

88.3 ± 12.7

69.4 ± 4.4

NO no renal involvement, MILD mild renal involvement, SEVERE severe renal involvement classified by ACR, SBP systolic blood pressure, DBP diastolic blood pressure, BMI body mass index, LDL-C low-density lipoprotein-cholesterol, ACR albumin creatinine ratio, FFA free fatty acid, H-CRP high-sensitive CRP, ASP acylation-stimulating protein, IL-18 interleukin 18, 8-OHdG 8-hydroxy-2-deoxyguanosine, L-FABP liver-type fatty acid binding protein

Value means M ± SE, * : statistically significant versus “NO” group

** : statistically significant versus “MILD” group

Table 2

Comparison of parameters among the severity of retinal involvement

 

NO

MILD

SEVERE

Total

Number of patients

26

14

8

48

SBP (mmHg)

121 ± 12

122 ± 6

130 ± 5

124 ± 12

DBP (mmHg)

76 ± 5

79 ± 3

80 ± 2

78 ± 4

BMI (kg/m2)

27.7 ± 0.3

26.9 ± 0.5

29.0 ± 2.0

27.7 ± 0.3

HbA1c (%)

7.0 ± 0.2

7.1 ± 0.2

6.5 ± 0.3

7.0 ± 0.1

LDL-C (mg/dl)

120 ± 5

100 ± 10

134 ± 7

117 ± 5

ACR (mg/g·Cr)

199 ± 94

396 ± 320

1,544 ± 741**

320 ± 109

FFA (μEq/l)

471 ± 42

404 ± 104

360 ± 217

452 ± 38

Cystatin C (mg/l)

0.8 ± 0.03

0.93 ± 0.07

1.31 ± 0.38**

0.86 ± 0.04

Adiponectin (μg/l)

4.6 ± 0.5

5.3 ± 1.5

4.0 ± 0.7

4.7 ± 0.5

H-CRP (ng/ml)

1,323 ± 312

1,321 ± 716

1,861 ± 841

1,356 ± 270

ASP (μg/dl)

183 ± 17

185 ± 29

317 ± 94**

192 ± 15

IL-18 (pg/ml)

343 ± 3

334 ± 5

343 ± 21

341 ± 3

8-OHdG (μg/g·Cr)

25.8 ± 6.3

26.9 ± 6.9

22.8 ± 3.9

24.2 ± 3.0

L-FABP (μg/g·Cr)

71.0 ± 5.6

65.1 ± 4.1

89.8 ± 9.6

69.4 ± 4.4

NO no retinal abnormality, MILD retinal vascular extravasation without proliferation, SEVERE retinal vascular extravasation and proliferation, SBP systolic blood pressure, DBP diastolic blood pressure, BMI body mass index, LDL-C low-density lipoprotein-cholesterol, ACR albumin creatinine ratio, FFA free fatty acid, H-CRP high-sensitive CRP, ASP acylation-stimulating protein, IL-18 interleukin 18, 8-OHdG 8-hydroxy-2-deoxyguanosine, L-FABP liver-type fatty acid binding protein

Value means M ± SE, * : statistically significant versus “NO” group

** : statistically significant versus “MILD” group

High-sensitive C-reactive protein (H-CRP) was measured by nephelometry [20]. IL-18, adiponectin (ADP), acylation-stimulating protein (ASP), L-FABP, and 8-OHdG were measured by enzyme-linked immunosorbent assay (ELISA) [21, 22, 23, 24, 25]. The assay kits were purchased from the following companies; IL-18: Medical & Biological Laboratories Co. Ltd., Nagoya, Japan, ADP: Fujirebio Inc, Tokyo, Japan, ASP: BD Biosciences, San Jose, CA, L-FABP: Immuno-Biological Laboratories Co. Ltd., Gunma, Japan, and 8-OHdG: Nikken SEIL Co. Ltd., Shizuoka, Japan. The other parameters were measured by the autoanalyzer at the central laboratory department of our hospital (e.g. plasma glucose by glucose oxidase immobilized oxygen electrode accelerated method, βN1-deoxyfructosyl hemoglobin (HbA1c) by latex agglutination method (LA), immuno reactive insulin (IRI) by chemiluminescent enzyme immuno assay (CLEIA), low-density lipoprotein-cholesterol (LDL-C) by direct measurement, FFA by gold colloid method, and ACR by immunoprecipitation).

The data obtained were statistically analyzed using JMP (SAS Institute Japan, Tokyo Japan). Differences between groups were significant at P < 0.05 by Student’s t-test. There were statistically significant correlations between groups at P < 0.05 by simple regression analysis.

Results

Of the parameters examined in this study, only the alterations of HbA1c and LDL-C were statistically correlated (P < 0.035). HbA1c was significantly increased in the “SEVERE” group of macroangiopathy in comparing with that in other macroangiopathy groups (P < 0.003) (Fig. 1). These data indicate that high HbA1c and high LDL-C would contribute to the development of macroangiopathy in type 2 diabetes mellitus.
Fig. 1

Difference in HbA1c levels between the severity of diabetic complications. HbA1c was significantly increased in the “Severe” group of macroangiopathy (P < 0.003) but was not increased in the microangiopathy group

The alterations in cystatin C, which is a marker of renal function, and ACR, which is a marker of renal injury, were significantly correlated (P < 0.001). The levels of cystatin C in each “SEVERE” microangiopathy group significantly increased (P = 0.035 in nephropathy, P = 0.050 in retinopathy, P = 0.003 in neuropathy). However, there was no increase in the macroangiopathy (Fig. 2). These data indicate that factors which contribute to the development of microangiopathy do not contribute to the development of macroangiopathy.
Fig. 2

Difference in cystatin C levels between the severity of diabetic complications. The levels of cystatin C in microangiopathy altered according to the severity (P = 0.035 in nephropathy, P = 0.050 in retinopathy, P = 0.003 in neuropathy) but was not increased in the macroangiopathy group

Proinflammatory cytokines play a role in the establishment of arteriolosclerosis [7, 8] and kidney injury [9, 10]. These cytokines also would contribute to the progression of diabetic nephropathy. H-CRP and IL-18 were significantly elevated in the “SEVERE” group of nephropathy in comparing with the “MILD” group (H-CRP: P = 0.0006, IL-18: P = 0.0159) (Table 1). These data indicate that proinflammatory cytokines and inflammation reaction are closely concerned with the progression of nephropathy but are not significantly concerned with other complications.

Oxidative stress also contributes to the occurrence of kidney injury [15, 17]. Urinary L-FABP and 8-OHdG, which are known stress markers of the kidney [16, 18], were elevated non-significantly in the “SEVERE” nephropathy group when compared with other group of severity (Table 1). These data indicate that oxidative stress and the ensuing inflammation slightly contribute the progression of nephropathy. However, in considering the weaker relationship between oxidative stress and nephropathy, the additional effect of IL-18 may also directly influence the progression of nephropathy.

A significant increase in ASP was detected in the “SEVERE” group of retinopathy, indicating possible retinal vascular proliferation in this study (P = 0.038) (Table 2). ASP was elevated in obese subjects and type 2 patients with diabetes with increased BMI and would be hypothesized to contribute to the progression of microangiopathy. However, there were no significant correlations between the severities of nephropathy and neuropathy. These data indicate that adipokines may more closely contribute to the progression of proliferative retinopathy.

Discussion

We measured alterations in the levels of cytokines in groups of patients representing different levels of severity of vascular complications in type 2 diabetes mellitus. Our results suggest a close relationship between IL-18 and kidney injury besides the acceleration of inflammation reaction due to oxidative stress and other proinflammatory cytokines in nephropathy. In addition, our results indicate a relationship between adipokines and retinal vascular proliferation. The development of macroangiopathy is independent of that of microangiopathy. As previously known [1, 3], the expression of macroangiopathy is related to hyperglycemia and hyperlipidemia in this study. The alteration pattern of cytokines suggests the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy.

Diabetes mellitus is well known as a risk factor for cardiovascular event and cerebrovascular disease. Glycemic control is critical for managing clinical complications in this disease [1, 26]. Dyslipidemia is also popularly known as a risk factor of diabetic complications [3, 27]. The occurrence pattern of vascular complications is different from each other. Our study indicates that the pathophysiological mechanism of each complication is similar but is not identical. Several parameters changed independently according to the disease stage and metabolic conditions, although the organ specificity may explain these discrepancies. Hypertension is poised to become a dangerous risk factor of diabetic complication [28, 29]. The hemodynamic influence on the heart and the kidney should be taken into account in evaluating the pathophysiology of diabetic microangiopathies. In this study, we controlled systemic and glomerular hypertension successfully by administering ARBs to all the patients on at least two visits prior to the start of this study. ARBs improve systemic hypertension by decreasing peripheral vascular resistance and decrease glomerular hypertension by relaxing efferent arteriole. Glycemic control, disease duration, and patients’ age may also play somewhat roles in the progression of glomerular complication; however, these factors may influence equally on other complication.

IL-18 and H-CRP significantly increased in the “SEVERE” nephropathy group. The inflammation reaction in glomerulus may occur more strongly than in arteriole. This may be explained by a similar mechanism occurring in primary glomerular disease and lupus nephritis. Previous reports indicate that transforming growth factor β (TGFβ) and interleukin 6 (IL-6) injure glomerular mesangial cells during the inflammation reaction [30, 31]. IL-18 is also known to have a proinflammatory effect in systemic lupus erythematosus [32, 33]. Increases in both the serum levels of, and resistance to, IL-18 have been reported in obese type 2 patients with diabetes [34]. Moreover, IL-18 has been reported to play a role in the formation of inflammation and endothelial dysfunction [35], and Wong et al. [36] reported that IL-18 was involved in renal dysfunction in non-diabetic patients. Tucci et al. [37] reported that IL-18 induced the accumulation of dendritic cells in the glomerulus, resulting in kidney injury. Araki et al. [19] reported predictive impact of IL-18 on diabetic renal dysfunction in a follow-up study. Several lines of evidence therefore implicate IL-18 in the direct induction of renal injury in diabetic nephropathy, in addition to its inflammatory effect and role in oxidative stress. Inflammatory events and oxidative stress are thought to occur in all diabetic complications [7, 8]. However, our study shows that the relationship between these parameters and the severity of vascular complications are not so closely correlated with their pathophysiology. This tendency can also be seen in the alteration pattern of urinary 8-OHdG and L-FABP. The increase in urine levels of these markers would indicate the existence of oxidative stress in vivo and predicts the existence of kidney injury in patients with diabetes [38]. This supports the existence of IL-18’s other pathological roles in addition to its oxidative effect.

Since cystatin C and ACR are correlated with the severity of other microangiopathies, a pathophysiology similar to nephropathy occurs in all the type 2 diabetic complications [39, 40]. In addition to inflammation reaction and oxidative stress, other factors were considered in the occurrence of microangiopathy. We examined adipokine levels and identified a correlation between plasma ASP and the severity of retinopathy, indicating that adipokines have an effect on the proliferation of retinal arterioles. The mechanism of vascular injury due to adipokines is different from the mechanism due to proinflammatory cytokines [41, 42]. There was no specific vascular finding in this study with regard to neuropathy.

In conclusion, we have identified some interesting differences in the pathophysiologies of different diabetes microangiopathies. Specifically, our results indicated that IL-18 has a direct role in the acceleration of glomerular injury in addition to its proinflammatory effect on this pathophysiology.

Notes

Acknowledgments

This work was supported in part by the fund of 50th anniversary of the foundation of Nihon University School of Medicine in 2007.

Conflicts of interest statement

All authors have no conflicts of interest.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Takayuki Fujita
    • 1
  • Norikazu Ogihara
    • 2
  • Yumi Kamura
    • 3
  • Atsushi Satomura
    • 4
  • Yoshinobu Fuke
    • 1
  • Chie Shimizu
    • 1
  • Yuki Wada
    • 1
  • Koichi Matsumoto
    • 1
  1. 1.Department of Nephrology, Hypertension and EndocrinologyNihon University School of MedicineItabashiku, TokyoJapan
  2. 2.Department of Diabetes and MetabolismNihon University School of MedicineItabashiku, TokyoJapan
  3. 3.Department of OphthalmologyNihon University School of MedicineItabashiku, TokyoJapan
  4. 4.Department of Laboratory MedicineNihon University School of MedicineItabashiku, TokyoJapan

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