Kunihiro Ichinose

Recent advancement of understanding pathogenesis of type 1 diabetes and potential relevance to diabetic nephropathy.

Type 1 diabetes mellitus is an autoimmune disease characterized by progressive destruction of pancreatic beta cells by genetic and environmental factors which leads to an absolute dependence of insulin for survival and maintenance of health. Although the majority of mechanisms of beta cell destruction remain unclear, many molecules, including proinflammatory cytokines and chemokines such as tumor necrosis factor alpha and monocyte chemoattractant protein-1, are implicated in the development of beta cell damage. Furthermore, beta cell destruction is enhanced by the Th1 and Th17 subsets of CD4+ T cells. In contrast, there are mechanisms involved in the maintenance of peripheral tolerance by regulatory T cells, the function of which depends on the pleiotropic cytokine transforming growth factor beta. Development and progression of renal injuries in patients with diabetic nephropathy are also associated with several growth factors and proinflammatory cytokines, including tumor necrosis factor alpha, insulin-like growth factor-1, monocyte chemoattractant protein-1, vascular endothelial growth factor, and transforming growth factor beta. Although the pathogenic mechanisms underlying type 1 diabetes and diabetic nephropathy are principally different, i.e., autoimmunity and inflammation, some common factors, including susceptibility genes and proinflammatory cytokines, are involved in both mechanisms, including infiltrating cell recruitment, upregulation of other cytokines and chemokines, or apoptosis.

2-(8-Hydroxy-6-Methoxy-1-Oxo-1H-2-Benzopyran-3-yl) Propionic Acid, an Inhibitor of Angiogenesis, Ameliorates Renal Alterations in Obese Type 2 Diabetic Mice

One of the mechanisms involved in the progression of diabetic nephropathy, the most common cause of end-stage renal failure, is angiogenic phenomenon associated with the increase of angiogenic factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2, an antagonist of Ang-1. In the present study, we examined the therapeutic efficacy of 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3), a small molecule isocoumarin with antiangiogenic activity, using diabetic db/db mice, a model of obese type 2 diabetes. Increases in kidney weight, glomerular volume, creatinine clearance, urinary albumin excretion, total mesangial fraction, glomerular type IV collagen, glomerular endothelial area (CD31+), and monocyte/macrophage accumulation (F4/80+) observed in control db/db mice were significantly suppressed by daily intraperitoneal injection of NM-3 (100 mg/kg, for 8 weeks). Increases in renal expression of VEGF-A, Ang-2, fibrogenic factor transforming growth factor (TGF)-β1, and chemokine monocyte chemoattractant protein-1 but not tumor necrosis factor-α were also inhibited by NM-3 in db/db mice. Furthermore, decreases of nephrin mRNA and protein levels in db/db mice were recovered by NM-3. In addition, treatment of db/db mice with NM-3 did not affect body weight, blood glucose, serum insulin, or food consumption. NM-3 significantly suppressed the increase of VEGF induced by high glucose in cultured podocytes and also suppressed the increase of VEGF and TGF-β induced by high glucose in cultured mesangial cells. Taken together, these results demonstrate the potential use of NM-3 as a novel therapeutic agent for renal alterations in type 2 diabetes.

Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase type IV.

OBJECTIVEnSystemic lupus erythematosus (SLE) is a chronic inflammatory disease associated with aberrant immune cell function. Treatment involves the use of indiscriminate immunosuppression, which results in significant side effects. SLE T cells express high levels of calcium/calmodulin-dependent protein kinase type IV (CaMKIV), which translocates to the nucleus upon engagement of the T cell receptor-CD3 complex and accounts for abnormal T cell function. The purpose of this study was to determine whether inhibition of CaMKIV would improve disease pathology.nnnMETHODSnWe treated MRL/lpr mice with KN-93, a CaMKIV inhibitor, starting at week 8 or week 12 of age and continuing through week 16 and evaluated skin lesions, proteinuria, kidney histopathology, proinflammatory cytokine production, and costimulatory molecule expression. We also determined the effect of silencing of CAMK4 on interferon-γ (IFNγ) expression by human SLE T cells.nnnRESULTSnCaMKIV inhibition in MRL/lpr mice resulted in significant suppression of nephritis and skin disease, decreased expression of the costimulatory molecules CD86 and CD80 on B cells, and suppression of IFNγ and tumor necrosis factor α production. In human SLE T cells, silencing of CAMK4 resulted in suppression of IFNγ production.nnnCONCLUSIONnWe conclude that suppression of CaMKIV mitigates disease development in lupus-prone mice by suppressing cytokine production and costimulatory molecule expression. Specific silencing of CAMK4 in human T cells results in similar suppression of IFNγ production. Our data justify the development of small-molecule CaMKIV inhibitors for the treatment of patients with SLE.

Cutting Edge: Calcium/Calmodulin-Dependent Protein Kinase Type IV Is Essential for Mesangial Cell Proliferation and Lupus Nephritis

Renal involvement in systemic lupus erythematosus remains a major cause of morbidity and mortality. Although immune parameters that instigate renal damage have been characterized, their link to local processes, which execute tissue damage, is poorly understood. Using genetic-deletion and pharmacological-inhibition approaches, we demonstrated that calcium/calmodulin-dependent protein kinase type IV, which contributes to altered cytokine production in systemic lupus erythematosus patients, controls spontaneous and platelet-derived growth factor-stimulated mesangial cell proliferation and promotes IL-6 production through AP-1. Our studies identified calcium/calmodulin-dependent protein kinase type IV as a valuable treatment target for lupus nephritis and point out the importance of local kidney factors in the expression of tissue damage that, if properly targeted, should enhance clinical benefit and limit toxicity.

Amelioration of cisplatin-induced acute renal injury by renal progenitor-like cells derived from the adult rat kidney

The replacement of a necrotic tubular epithelium with functional tubular epithelial cells is required for recovery from acute renal failure (ARF). A rat renal progenitor-like (rKS56) cell line was recently established derived from the S3 segment of renal proximal tubules. The therapeutic efficacy of rKS56 cells was examined in a rat model of cisplatin-induced ARF. rKS56-lacZ cells expressing β-galactosidase were injected into SD rats either at the subcapsule of the left kidney (rKS-SC) or via the left renal artery (rKS-IA) 2 days after the injection of cisplatin. Bluo-gal(+) rKS56-lacZ cells were observed in the subcapsule in the rKS-SC group on day 5, and were further increased in number on day 9, accompanied by partial distribution in the corticomedullary junction, but not in the rKS-IA group. A portion of Bluo-gal(+) cells coexpressed Ki-67, aquaporin-1, hepatocyte growth factor (HGF), and c-Met. rKS-SC treatment significantly improved the tubular injury scores, ameliorated tubular cell apoptosis, and induced cell proliferation. The renal function also significantly improved in the rKS-SC group on day 5. These results demonstrate that locally implanted rKS56 cells could differentiate into tubular epithelial cells, thereby accelerating the recovery from tubular injury, most likely by producing tubular trophic factors. These results suggest the therapeutic potential of this novel approach for patients with end-stage renal failure.

Consultants for the American Journal of Nephrology 2007

Mario Cozzolino Farhard Danesh Robert Danziger John Daugirdas Katherine Dell Luca De Nicola Janice Douglas Thomas DuBose Carolyn Ecelbarger Allison Eddy Charles Edelstein Beatrice Edwards Belkıs Erbas Ronald Falk Ken Farrington Sahar Fathallah-Shaykh Murray Favus Leon Ferder Albert Ferro Michael Fischer Steven Fishbane Barry Freedman Gordon Freeman Elena Gagliardini C. Garlichs Fumitake Gejyo P. Gentilini Cheryl Gilmartin Richard Glassock Ehud Goldhammer David Goldsmith Stuart Goldstein Jennifer Gooch Laurence Greenbaum Dimitrios Grekas Hans Grosse-Wilde Mehmet Haberal Peter Hart Tomoko Hayashida Peter Heering Klaus Hocherl Radovan Hojs Susan Hou Priscilla How Reiko Inagi Ajay Israni Edwin Jackson Sara Jandeska Vanita Jassal Kevin Abbott Dale Abrahamson Adel Afifi Rajiv Agarwal Cu-Rie Ahn Maie Albader Farah Ali Ahsan Arozullah John Asplin Brad Astor Aslihan Avci Carla Avesani Mindy Banks Vinod Bansal Mary Barchman Amelia Bartholomew Amy Barton Pai David Basile F. Baud John Beltrame Carsten Bergmann Rajendra Bhimma Daniel Bichet Peter Blake Amy Bobrowski W. Kline Bolton Michael Braun Carolyn Brecklin Ellen Brooks Edward Brown Vito Campese Caterina Canavese Zemin Cao Lucio Cardoso Daniel Catanzaro Tak Mao Chan Rene Chang Julie Chao Monique Cho Yongwon Choi Nina Clark Steven Coca David Cohen Gabriel Contreras Mark Cooper Dominic Cosgrove Scott Cotler Adrian Covic Daniel Coyne