The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes.

OBJECTIVE: Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes. METHODS: Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation. RESULTS: Gemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis. CONCLUSION: Gemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes.

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.

Mycophenolate Mofetil Ameliorates Diabetic Nephropathy in db/db Mice.

Chronic low-grade inflammation is an important factor in the pathogenesis of diabetic complication. Mycophenolate mofetil (MMF) has an anti-inflammatory effect, inhibiting lymphocyte proliferation. Previous studies showed attenuation of diabetic nephropathy with MMF, but the underlying mechanisms were unclear. This study aimed to identify the effect of MMF on diabetic nephropathy and investigate its action mechanisms in type 2 diabetic mice model. Eight-week-old db/db and control mice (db/m mice) received vehicle or MMF at a dose of 30 mg/kg/day for 12 weeks. MMF-treated diabetic mice showed decreased albuminuria, attenuated mesangial expansion, and profibrotic mRNA expressions despite the high glucose level. The number of infiltrated CD4(+) and CD8(+) T cells in the kidney was significantly decreased in MMF-treated db/db mice and it resulted in attenuating elevated intrarenal TNF-α and IL-17. The renal chemokines expression and macrophages infiltration were also attenuated by MMF treatment. The decreased expression of glomerular nephrin and WT1 was recovered with MMF treatment. MMF prevented the progression of diabetic nephropathy in db/db mice independent of glycemic control. These results suggest that the effects of MMF in diabetic nephropathy are mediated by CD4(+) T cell regulation and related cytokines.

Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression.

Proinflammatory T helper 1 (Th1) and T helper 17 (Th17) cell subsets have been reported to have an immunopathogenic role in metabolic disease. We previously demonstrated that CD4(+) T cells are increased in kidneys in type 2 diabetic patients. However, the role of Th1 and Th17 cells in the development and progression of diabetic nephropathy is unclear. In this study, we examined the hypothesis that mycophenolate mofetil (MMF) attenuates diabetic kidney injury by the suppression of renal T-cell proliferation and related cytokines. Four groups of male C57/BL6 mice (8-weeks-old) were studied: (1) untreated controls, (2) MMF-treated controls (30 mg/kg of body weight per day), (3) streptozotocin (STZ)-induced diabetes, and (4) MMF-treated STZ-induced diabetes. The interferon gamma (IFN-γ) and interleukin 17 (IL-17) from renal CD4(+) T cells were analyzed in kidney mononuclear cells by flow cytometry. We found proliferating CD4(+) T cells were significantly increased in the kidney compared with the spleen. There were increases in IFN-γ(+) CD4(+) and IL-17A(+) CD4(+) T cells from the initiation of albuminuria in the kidneys of diabetic mice. We found MMF suppresses only the intrarenal IL-17A(+) CD4(+) T cells from early diabetic nephropathy and improves albuminuria, tubulointerstitial fibrosis independent of glycemic control. Our study results suggest that Th17 may play an independent role in the progression of diabetic nephropathy and modulation of IL-17 has potential as an immunologic therapeutic target.

Validation study of peripheral blood diagnostic test for acute rejection in kidney transplantation.

BACKGROUND: Diagnosing acute rejection (AR) in kidney transplant recipients typically requires an invasive kidney biopsy. A previous study has suggested that expression of five genes in peripheral blood can indicate the presence of AR in American pediatric kidney transplant recipients. This study aims to validate if these five genes are also useful to diagnose AR in Korean adult kidney transplant patients. METHODS: Blood samples were collected from 143 patients (39 biopsy-proven AR, 84 stable patients, and 20 other graft injuries) at an average of 9 months posttransplantation and performed real-time PCR for five-gene biomarkers (DUSP1, NKTR, MAPK9, PSEN1, and PBEF1). RESULTS: Patients with acute cellular rejection (ACR) had a significantly decreased level of MAPK9 and a significantly increased level of PSEN1 when compared with controls and also with patients with other graft injury (OGI). In multivariate logistic regression analysis, for discrimination between ACR and OGI, an excellent diagnostic accuracy was observed in the gene sets but five-gene set generated a higher AUC than two-gene set. With clinical variables combined to these gene sets, the diagnostic accuracy increased in both five-gene set and two-gene set. CONCLUSIONS: These results support the validity of 5 gene-set for the prediction of AR in Asian adult kidney transplant recipients and suggest the promising role of the peripheral blood gene test in the diagnosis of AR in kidney transplantation.