Urinary chemokine C-X-C motif ligand 16 and endostatin as predictors of tubulointerstitial fibrosis in patients with advanced diabetic kidney disease.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. METHODS: Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. RESULTS: Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070-3.455, P = 0.029). CONCLUSIONS: Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

CCL24 Signaling in the Tumor Microenvironment.

Chemokines with their network play an important role in cancer growth, metastasis, and host-tumor interactions. Of many chemokines, C-C motif chemokine ligand 24 (CCL24) has been shown to contribute to tumorigenesis as well as inflammatory diseases like asthma, allergies, and eosinophilic esophagitis. CCL24 is expressed in some tumor cells such as colon cancer, hepatocellular carcinoma, and cutaneous T cell lymphoma. CCL24 can be used as a potential biomarker in several cancers including colon cancer, non-small cell cancer, and nasopharyngeal carcinoma as the plasma level of CCL24 is increased. The various functions of CCL24 contribute to the biology of cancer by M2 macrophage polarization, angiogenesis, invasion and migration, and recruitment of eosinophils.

Growth and Bone Mineral Density Changes in Ovariectomized Rats Treated with Estrogen Receptor Alpha or Beta Agonists.

BACKGROUND: Estrogen controls the pubertal growth spurt, growth plate closure, and accretion of bone mineral density (BMD) of long bones after biding estrogen receptor (ER). There are two subtypes of ER, ERα and ERß. If each ER subtype has different effects, we may control those actions by manipulating the estrogen binding intensity to each ER subtype and increase the final adult height without markedly reducing BMD or impairing reproductive functions. The purpose of our study was to compare these effects of ERα and ERß on long bones in ovariectomized rats. METHODS: Thirty female rats were ovariectomized and randomly divided into 3 groups. The control, propylpyrazole triol (PPT), and 2,3-bis (4-hydroxyphenyl) propionitrile (DPN) groups were subcutaneously injected for 5 weeks with sesame oil, PPT as an ERα agonist, and DPN as an ERß agonist, respectively. The crown-lump length and body weight were measured weekly. BMD, serum levels of growth hormone (GH) and estradiol were checked before and after 5 weeks of injections. Pituitary GH1 expression levels were determined with quantitative real-time polymerase chain reaction, the proximal tibias were dissected, decalcified and stained with hematoxylin-eosin, and the thicknesses of epiphyseal plates including proliferative and hypertrophic zones were measured in 20-evenly divided sites after 5 weeks of injections. Comparisons for auxological data, serum hormone and pituitary GH1 expression levels, BMD, and epiphyseal plate thicknesses among 3 groups before and after injections were conducted. RESULTS: There was no significant difference in body lengths among 3 groups. The body weights were significantly lower, but, serum GH, pituitary GH1 expression levels, and BMDs were higher in PPT group than the other 2 groups after 5 weeks of injections. There was no significant difference in the thicknesses of the total epiphyseal plate, proliferative, and hypertrophic zone among 3 groups. CONCLUSION: ERα is more involved in pituitary GH secretion and bone mineral deposition than ERß. Weight gain might be prevented with the ERα agonist.

Recurrent breast amyloidosis associated with Sjögren's syndrome: A case report with description of the radiologic-pathologic correlation.

We describe the case of a 41-year-old woman with primary Sjögren's syndrome (SS) who presented multiple recurrences of breast amyloidosis. Each recurrence of breast amyloidosis showed different sonographic features, potentially mimicking malignancy. We briefly discuss the possible cause of this variability in imaging features based on the radiologic-histologic correlation.

Alterations in Lipid Profile of the Aging Kidney Identified by MALDI Imaging Mass Spectrometry.

During aging, the kidney undergoes functional and physiological changes that are closely affiliated with chronic kidney disease (CKD). There is increasing evidence supporting the role of lipid or lipid-derived mediators in the pathogenesis of CKD and other aging-related diseases. To understand the role of lipids in various metabolic processes during kidney aging, we conducted matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) analysis in kidneys harvested from young (2 months old, n = 3) and old mice (24 months old, n = 3). MALDI-IMS analysis showed an increase in ceramide level and a decrease in sphingomyelin (SM) and phosphatidylcholine (PC) levels in kidneys of old mice. The increased expression of cPLA2 and SMPD1 protein in aged kidney was confirmed by immunohistochemistry and Western blot analysis. Our MALDI-IMS data showed the altered distribution of lipids in aged kidney as indicative of aging-related functional changes of the kidney. Combined analysis of MALDI-IMS and IHC confirmed lipidomic changes and expression levels of responsible enzymes as well as morphological changes.

Sonographic Diagnosis of a Colovesical Fistula Due to Sigmoid Colon Cancer.

Based on sonographic findings, colovesical fistula was diagnosed in a 71-year-old man with sigmoid colon cancer. Gray-scale sonography revealed an irregular thickening of the sigmoid colon wall abutting the urinary bladder which also showed thickening in the region of contact. Color Doppler sonography showed a twinkling artifact within the thickened bladder wall. Contrast-enhanced computed tomography scan showed luminal communication between the sigmoid colon and the bladder in the region of thickening.

Sequential activation of the intrarenal renin-angiotensin system in the progression of hypertensive nephropathy in Goldblatt rats.

The intrarenal renin-angiotensin system (RAS) has an important role in generating and maintaining hypertension in two-kidney, one-clip (2K1C) rats. This study evaluated how various intrarenal RAS components contributed to hypertension not only in the maintenance period (5w; 5 wk after operation) but also earlier (2w; 2 wk after operation). We inserted a 2.5-mm clip into the left renal artery of Sprague-Dawley rats and euthanized them at 2w and 5w following the operation. Systolic blood pressure increased within 1 wk after the operation, and left ventricular hypertrophy occurred in 2K1C rats. At 2w, juxtaglomerular apparatus (JGA) and collecting duct (CD) renin increased in clipped kidney (CK) of 2K1C rats. The tubular angiotensin I-converting enzyme (ACE) was not changed, but peritubular ACE2 decreased in nonclipped kidney (NCK) and CK of 2K1C rats. At 5w, ACE and CD renin were enhanced, and ACE2 was still lessened in both kidneys of 2K1C rats. However, plasma renin activity (PRA) was not different from that in sham rats. In proximal tubules of CK, the ANG II type 1 receptor (AT1R) was not suppressed, but the Mas receptor (MasR) was reduced; thus the AT1R/MasR ratio was elevated. Although hypoxic change in CK could not be excluded, the JGA renin of CK and CD renin in both kidneys was highly expressed independent of time. Peritubular ACE2 changed in the earlier period, and uninhibited AT1R in proximal tubules of CK was presented in the maintenance period. In 2K1C rats, attenuated ACE2 seems to contribute to initiating hypertension while upregulated ACE in combination with unsuppressed AT1R may have a key role in maintaining hypertension.

Complete Remission of Nephrotic Syndrome Without Resolution of Amyloid Deposit After Anti-Tumor Necrosis Factor α Therapy in a Patient With Ankylosing Spondylitis.

In secondary amyloid A amyloidosis resulting from rheumatologic diseases, tumor necrosis factor α blockers have been reported to be effective in the treatment of both arthritis and amyloidosis. However, there have been few reports concerning the alterations of renal tissue histology before and after long-term tumor necrosis factor α blockers therapy in secondary renal amyloidosis. We report the histological change after tumor necrosis factor α blocker therapy in patient with amyloid A amyloidosis and nephrotic syndrome secondary to underlying ankylosing spondylitis. The patient achieved complete remission of nephrotic syndrome after 17 months of etanercept treatment. We performed the second kidney biopsy after 40 months, and there was little change in the degree of amyloid deposition in the mesangial area and capillary loops compared with the first biopsy. The interstitial inflammation and foot process effacement, however, were fully recovered.

Amelioration of trinitrobenzene sulfonic acid-induced colitis in mice by liquiritigenin.

BACKGROUND AND AIM: The anti-inflammatory effects of liquiritigenin, a major flavonoid isolated from Glycyrrhizae uralensis, have been reported in many inflammation models. However, its protective effects have not been reported in a colitis model. This study investigated the anti-inflammatory effect and mechanism of liquiritigenin for trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. METHODS: Male mice imprinting control regions (ICR) were randomly divided into five groups: normal, TNBS-induced colitis, colitis treated with liquiritigenin at low dose (10 mg/kg) and high dose (20 mg/kg), or mesalazine (10 mg/kg). TNBS colitis induction was performed except for in the normal group, and they were treated with liquiritigenin or mesalazine except control group. The treatment effect was measured after three days treatment, by body weight, colon length, macroscopic score, histological score, levels of cytokines (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, and IL-10) in colon tissue as well as the nuclear factor kappa-light-chain-enhancer pathway of activated B cells (NF-κB) activation. RESULTS: Mice treated with high-dose liquiritigenin showed significant body weight gain, inhibition of colon shortening, protective effect on histological damages, and myeloperoxidase activity of colon tissue compared with the control group. Furthermore, mice treated with high-dose liquiritigenin experienced significantly suppressed tumor necrosis factor-α, IL-1ß, and IL-6 as well as enhanced IL-10 expression (all P < 0.05). High-dose liquiritigenin treatment group showed significant decreases in TNBS-induced phosphorylation of IKKß, p65, and IκB-α. CONCLUSION: Liquiritigenin may ameliorate TNBS-induced colitis in mice by suppressing expression of pro-inflammatory cytokines through NF-κB pathway.

Sonographic findings of tuberculous vasitis.

The purpose of this series was to describe the sonographic findings of tuberculous vasitis. We conducted a retrospective analysis of 3 cases of tuberculous vasitis. The following grayscale and color Doppler sonographic features were analyzed: location, echogenicity of the lesion, epididymal or testicular involvement, presence of hydrocele, and blood flow within the lesion. All 3 patients had focal (n = 2) or multifocal (n = 1) involvement of the scrotal segment of the vas deferens. The sonographic findings for tuberculous vasitis were heterogeneously hypoechoic in all of the cases. On color Doppler sonography, no blood flow was identified within the lesions of the vas deferens. All 3 patients had tuberculous epididymitis in addition to tuberculous vasitis. Tuberculous vasitis presents with infection along with tuberculous epididymitis, and it appears as a heterogeneously hypoechoic lesion in the scrotal segment of the vas deferens adjacent to the epididymal tail.

Intramuscular diffuse-type tenosynovial giant cell tumor of the deltoid muscle in a child.

Tenosynovial giant cell tumors (GCTs) typically form in the joints or extra-articular soft tissues such as the tendon sheath, and are benign tumors that commonly occur in the hands or wrists in the third to fifth decades of life. However, the diffuse type of extra-articular GCT arising within muscle is a rare soft tissue tumor, especially in a pediatric patient. In this report, we describe the magnetic resonance imaging and sonographic findings of a rare case of intramuscular diffuse-type GCT in the deltoid muscle of a 9-year-old boy.

Prophylactic effects of Lonicera japonica extract on dextran sulphate sodium-induced colitis in a mouse model by the inhibition of the Th1/Th17 response.

Inflammatory bowel diseases (IBD) are chronically relapsing inflammatory disorders of the intestine. Although some therapeutic agents, including steroids, are available for the treatment of IBD, these agents have limited use. Therefore, dietary supplements have emerged as possible interventions for IBD. Japanese honeysuckle flower, the flower of Lonicera japonica, is a well-known dietary supplement and has been used to prevent or treat various inflammatory diseases. In the present study, we investigated the effects of L. japonica on experimental murine colitis. Colitis was induced by 5 % dextran sulphate sodium (DSS) in Balb/c mice. The water extract of L. japonica (LJE) at doses of 20, 100 or 500 mg/kg was orally administered to mice twice per day for 7 d. Body weight, colon length and a histological damage score were assessed to determine the effects on colitis. Cytokine profiles were assessed to examine the effects on helper T (Th) cell-related immunological responses. In addition, CD4⁺CD25⁺Foxp3⁺T cells were analysed in vivo and in vitro for investigating the effects on regulatory T (Treg) cells. LJE showed dose-dependent inhibitory effects against colon shortening, weight loss and histological damage. LJE down-regulated IL-1ß, TNF-α, interferon-γ, IL-6, IL-12 and IL-17. However, LJE did not show any significant effects on IL-10, IL-23, transforming growth factor-ß1 and Treg cell populations. In conclusion, LJE showed protective effects against DSS-induced colitis via the Th1/Th17 pathway and not via Treg cell-related mechanisms.

Renal involvement in ankylosing spondylitis: prevalence, pathology, response to TNF-a blocker.

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily involving the spine and sacroiliac joint and rarely the kidneys. This study aimed to define the clinical and histological features and biology of renal disease in AS. We reviewed the medical records of 681 patients diagnosed with AS from November 2008 to November 2009. Baseline characteristics and laboratory and urinalysis results were reviewed. We identified patients with proteinuria or hematuria and analyzed their risk factors. After providing informed consent, 6 patients underwent a renal biopsy to determine the cause of proteinuria or hematuria. Of the 681 enrolled patients, 547 were men and 134 were women; 81 % were HLA B27 positive, and 8 % had abnormal urinalysis findings (proteinuria, 5.9 %; hematuria, 2.8 %; both, 0.7 %). Incidences of peripheral arthritis and uveitis were 29 % and 18.6 %, respectively. Immunoglobulin (Ig)A and uric acid levels were significantly different between patients with and without proteinuria. Erythrocyte sedimentation rate (ESR), total cholesterol, creatinine, and C-reactive protein (CRP) levels were not statistically significantly different between the 2 groups nor were there any significant differences in IgA, uric acid, ESR, total cholesterol, creatinine, and CRP levels between patients with and without hematuria. Six patients who had >1 g/day proteinuria underwent a renal biopsy; 2 were diagnosed with IgA nephropathy, 1 with amyloidosis, and 3 with non-specific glomerulonephropathy. In the amyloidosis patient, severe proteinuria was the dominant feature. For patients with renal amyloidosis and other forms of glomerulonephritis who initially had normal creatinine levels, tumor necrosis factor (TNF)-alpha blocker therapy resolved proteinuria, but this was not the case for patients with initial renal insufficiency. Renal involvement is not a rare complication of AS, and prognoses differ depending on kidney pathology. Serum levels of uric acid and IgA may predict renal involvement in AS. In cases where abnormal urine sediment is identified, renal biopsy is required to determine prognosis and decide the treatment protocol. Baseline serum creatinine level is important for predicting treatment response.

Malignant Transformation of Warthin Tumor in the Cervical Lymph Node.

ABSTRACT: Warthin tumor is the second most common benign tumor of salivary glands. Here we present an interesting case of squamous cell carcinoma arising from the Warthin tumor in the cervical lymph node. The patient had another Warthin tumor in the parotid gland as well. Both the malignant transformation of Warthin tumor and the heterotopic occurrence of Warthin tumor in the cervical lymph node are rare. This exceptionally rare case demonstrates that the 2 rare clinical entities can occur simultaneously and affect clinical decisions.

Aberrant recruitment and activation of T cells in diabetic nephropathy.

BACKGROUND/AIMS: Recent evidence has shown that an inflammatory process is involved in the development and progression of diabetic nephropathy. This study examined the impact of activated intrarenal lymphocytes in this inflammatory process. METHODS: We studied T cell recruitment in mice with streptozotocin (STZ)-induced diabetes by flow cytometry and immunohistochemistry. The kidney biopsy specimens from patients with type 2 diabetes mellitus and diabetic nephropathy were evaluated by immunohistochemistry. RESULTS: In flow cytometry, intrarenal CD3+ T cells were significantly increased in proteinuric mice at 20 weeks after STZ injection. However, the population of T cells and B cells in diabetic spleen was not different from that of control mice. Immunohistochemistry also showed a marked infiltration of interstitial CD4+, CD8+ T cells in diabetic kidney. Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) mRNA expression was significantly increased in diabetic mouse kidney compared with controls. Interestingly, flow cytometry analysis of kidney-derived mononuclear cells from diabetic mice showed significantly increased production of IFN-γ and TNF-α by CD3+ T cells. Type 2 diabetic patients also showed a marked increase in CD4+, CD8+ and CD20+ cells in interstitium, and the number of CD4+ and CD20+ cells correlated with the amount of proteinuria. CONCLUSION: Our results clearly showed that aberrant intrarenal infiltration and the activation of T cells in interstitium are the underlying immunopathological mechanisms of diabetic kidney injury.

Expression of the mammalian target of rapamycin pathway markers in lung adenocarcinoma and squamous cell carcinoma.

OBJECTIVE: We investigated whether the expression of mammalian target of rapamycin (mTOR) pathway components is associated with clinicopathologic characteristics and patient outcome in lung adenocarcinoma (AC) and squamous cell carcinoma (SCC). METHODS: We used immunohistochemistry to evaluate the expression of phosphorylated Akt (pAkt), mTOR, p70 ribosomal protein S6 kinase (p70S6K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in 91 cases of AC and 154 cases of SCC. RESULTS: pAkt expression was positively correlated with the expression of mTOR (p < 0.001) and p70S6K (p < 0.001), and mTOR expression was positively correlated with p70S6K expression (p < 0.001). PTEN expression was inversely correlated with the expression of pAkt (p = 0.001), mTOR (p < 0.001) and p70S6K (p = 0.012). In addition, loss of PTEN expression, observed in 37.4% (34/91) of AC patients, was significantly associated with a higher histologic grade (p = 0.013), pathologic T stage (p = 0.016) and N stage (p < 0.001) and advanced TNM stage (p = 0.001), as well as a shorter overall survival of AC patients (p = 0.015). CONCLUSION: The high prevalence of PTEN loss and its association with aggressive tumor behavior and poor patient outcome in AC suggest that loss of PTEN expression is involved in AC progression and serves as a prognostic marker for patients with AC.

Reducing serum uric acid attenuates TGF-ß1-induced profibrogenic progression in type 2 diabetic nephropathy.

BACKGROUND: The pivotal role of transforming growth factor-ß1 (TGF-ß1)-induced tubulointerstitial fibrosis in the progression of chronic kidney disease is an active topic of research. Recent evidence indicates that hyperuricemia is associated with increased TGF-ß1 and progressive tubulointerstitial injury. We examined the hypothesis that lowering serum uric acid attenuates TGF-ß1-induced profibrogenic tubular change in type 2 diabetic nephropathy. METHODS: KK-A(y)/Ta mice, an animal model of type 2 diabetes, were provided access to either regular drinking water or drinking water containing 10 mg/dl of allopurinol. Normal rat kidney epithelial cells were cultured and stimulated with 5 mM uric acid with or without allopurinol. RESULTS: Type 2 diabetic mice that received allopurinol exhibited smaller increases in urinary albumin:creatinine ratio than diabetic control mice, as well as attenuated TGF-ß1 and Smad pathway-induced profibrogenic tubular changes in diabetic kidneys. Allopurinol attenuated TGF-ß1-induced Smad pathway activation in tubular cells. These findings were related to increases in E-cadherin, and decreases in vimentin and α-smooth muscle actin. Uric acid-induced upregulation of TGF-ß1 depends on mitogen-activated protein kinase signaling. CONCLUSIONS: This is the first study to demonstrate that reducing serum uric acid has preventive effects against to profibrogenic progression in type 2 diabetic kidney disease. These findings suggest that lowering serum uric acid may be an effective therapeutic intervention to prevent the progression of type 2 diabetic kidney disease.

Correlation between FDG uptake by PET/CT and the expressions of glucose transporter type 1 and hexokinase II in cervical cancer.

BACKGROUND: The aim of this study was to explore the association between 2-deoxy-2-F18-fluoro-D-glucose uptake and the expressions of glucose transporter type 1 (GLUT-1) and hexokinase II (HK-II) in the lymph nodes of patients with cervical cancer. METHODS: This prospective study included 20 women with International Federation of Gynecology and Obstetrics stage IB to stage IIA cervical cancer who underwent positron emission tomography (PET)-computed tomography (CT) (PET/CT) before surgical treatment. In 333 dissected lymph nodes (LNs) obtained, we examined the size, tumor involvement, and expressions of GLUT-1 and HK-II. These characteristics were compared with PET/CT and pathological findings. RESULTS: Pathological analysis found that 21% (70) of the 333 surgically dissected LNs were metastatic. Positron emission tomography/CT detected metastasis with 22.8% sensitivity and 98.5% specificity. The levels of GLUT-1 and HK-II expression in false-positive LNs were higher than those in pathologically confirmed negative nodes (P = 0.015 and P = 0.001, respectively). In metastatic LNs, PET/CT-positive nodes were significantly different from PET/CT-negative nodes in mean size (P = 0.043), tumor involvement (P = 0.008), and proportion of GLUT-1-positive tumor cells (P = 0.042). CONCLUSIONS: Our results indicate that overexpression of GLUT-1 and HK-II may be related to 2-deoxy-2-F18-fluoro-D-glucose uptake in false-positive tissues on PET/CT. In metastatic lymph nodes, the ability of PET/CT to detect cancer may depend on tumor involvement, lymph node size, and GLUT-1 expression.

Sonographic findings of fibrous pseudotumor of the tunica vaginalis.

We report the sonographic findings in a case of fibrous pseudotumor of the tunica vaginalis. Scrotal gray-scale sonography revealed a well-margined, hypoechoic mass with an onion ring appearance and central calcifications in the left scrotum. Color Doppler sonography showed no blood flow within the mass. The pathological examination revealed a fibrous pseudotumor with a paucicellular and fibroblastic proliferation of cells within a hyalinized collagenous stroma.

Attenuating effect of angiotensin-(1-7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-A(y)/Ta mice.

ANG-(1-7) is associated with vasodilation and nitric oxide synthase stimulation. However, the role of ANG-(1-7) in type 2 diabetes mellitus is unknown. In this study, we examined the hypothesis that ANG-(1-7) attenuates ANG II-induced reactive oxygen species stress (ROS)-mediated injury in type 2 diabetic nephropathy of KK-A(y)/Ta mice. KK-A(y)/Ta mice were divided into four groups: 1) a control group; 2) ANG II infusion group; 3) ANG II+ANG-(1-7) coinfusion group; and 4) ANG II+ANG-(1-7)+d-Ala(7)-ANG-(1-7) (A779) coinfusion group. In addition, primary mesangial cells were cultured and then stimulated with 25 mM glucose with or without ANG II, ANG-(1-7), and A779. The ANG II+ANG-(1-7) coinfusion group showed a lower urinary albumin/creatinine ratio increase than the ANG II group. ANG-(1-7) attenuated ANG II-mediated NAD(P)H oxidase activation and ROS production in diabetic glomeruli and mesangial cells. ANG II-induced NF-κB and MAPK signaling activation was also attenuated by ANG-(1-7) in the mesangial cells. These findings were related to improved mesangial expansion and to fibronectin and transforming growth factor-ß1 production in response to ANG II and suggest that ANG-(1-7) may attenuate ANG II-stimulated ROS-mediated injury in type 2 diabetic nephropathy. The ACE2-ANG-(1-7)-Mas receptor axis should be investigated as a novel target for treatment of type 2 diabetic nephropathy.