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Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix and involved in ischemic organ injuries. The present study was designed to determine the role of MMP-2 in the development of ischemic acute kidney injury (AKI). AKI was induced in MMP-2 wild-type (MMP-2 þ / þ ) mice by 30, 60, 90, and 120 min renal ischemia and reperfusion. Renal histology, expression and activity of MMP-2 and MMP-9, and renal function were examined during the development of AKI. AKI was also induced in MMP-2-deficient (MMP-2 À/À ) mice and MMP-2 þ / þ mice treated with inhibitor of MMPs (minocycline and synthetic peptide MMP inhibitor). In MMP-2 þ / þ mice, MMP-2 and MMP-9 activities increased significantly at 2 to 24 h, peaked at 6 h, after reperfusion. Immunohistochemical analysis identified MMP-2 in the interstitium around tubules and peritubular capillaries in the outer medulla. Acute tubular injury (ATI), including apoptosis and necrosis, was evident in the outer medulla at 24 h, along with renal dysfunction. As ischemia period increases, MMP-2 and MMP-9 activities at 6 h and severity of AKI at 24 h increased depending on the duration of ischemia between 30 and 120 min. However, the kidneys of MMP-2 À/À mice showed minimal ATI; serum creatinine 24 h after reperfusion was significantly low in these mice. Inhibitors of MMPs reduced ATI and improved renal dysfunction at 24 h. We conclude that MMPs, especially MMP-2 have a pathogenic role in ischemiareperfusion AKI, and that inhibitors of MMPs can protect against ischemic AKI. KEYWORDS: acute kidney injury; acute tubular injury; ischemia/reperfusion; MMP-2; MMP-9; MMP inhibitor Ischemia-reperfusion acute kidney injury (AKI) remains a major cause of morbidity and mortality.1-5 The pathophysiology of AKI is complex; the initial ischemia and reperfusion events rapidly lead to energy loss, which ultimately triggers a wide and intricately linked cascade of tubular epithelial cell death pathways. Over the past decade, various molecular mechanisms have been implicated, including activation of Ca 2 þ -dependent proteases or other enzymes, oxidative stress, and even programmed cell death signals, such as apoptosis. [6][7][8] In addition to these primarily intracellular events, evidence for the importance of intercellular signaling is beginning to emerge, all cells in the renal tubular and microvasculature are also affected, not just tubular epithelial cells.6-10 Renal tubulovascular perturbations in AKI lead to tubular damage, back leak, obstructive cast formation, leukocyte infiltration, and altered renal microvascular function that contribute to the development of AKI over hours or days after ischemia-reperfusion.Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases responsible for extracellular matrix turnover, as well as degradation of bioactive proteins. 11,12 This family includes collagenases, gelatinases, stromelysins, and membranetype MMPs. Recently, MMPs, especially gelatinases (MMP-2 and MMP-9) have been demonstrated to have major roles i...

Thrombotic microangiopathy (TMA) is a major complication after hematopoietic stem cell transplantation (HSCT). In this study, we examined the clinical and pathologic features of 2 patients and 5 autopsy cases with HSCT-associated renal TMA to clarify the association between graft-versus-host disease (GVHD) and renal TMA. The median interval between HSCT and renal biopsy or autopsy was 7 months (range 3-42 months). Clinically, acute and chronic GVHD occurred in 7 and 4 patients, respectively. Clinical evidence for TMA was detected in 2 patients, while chronic kidney disease developed in all patients. The main histopathological findings were diffuse endothelial injury in glomeruli, peritubular capillaries (PTCs), and small arteries. In addition, all cases showed glomerulitis, renal tubulitis, and peritubular capillaritis with infiltration of CD3+ T cells and TIA-1+ cytotoxic cells, suggesting that GVHD occurred during the development of TMA. Diffuse and patchy C4d deposition was noted in glomerular capillaries and PTCs, respectively, in 2 biopsy and 2 autopsy cases, suggesting the involvement of antibody-mediated renal endothelial injury in more than 50% of renal TMA cases. In conclusion, the kidney is a potential target of chronic GVHD that may induce the development of HSCT-associated TMA. Importantly, some cases are associated with chronic humoral GVHD.

ϩ macrophages, with a few CD4 ϩ cells infiltrating the glomeruli. Necrotizing and crescentic glomerular lesions developed by day 7 with the increase of proteinuria. AT 1R was expressed on CD8 ϩ and CD4 ϩ cells and on ED1 ϩ macrophages. Low-dose ARB had no anti-inflammatory effects in anti-GBM GN. However, highdose ARB reduced glomerular infiltration of CD8 ϩ cells and ED1 ϩ macrophages and suppressed necrotizing and crescentic lesions by days 5 to 7 (P Ͻ 0.05). In addition, high-dose ARB reduced the numbers of ED3 ϩ -activated macrophages, suppressed glomerular TNF-␣ and IFN-␥ production, and downregulated M1-related chemokine and cytokines (monocyte chemoattractant protein type 1, IL-6, and IL-12). High-dose ARB also enhanced ED2 ϩ M2 macrophages by day 7 with upregulation of glomerular IL-4 and IL-13 and augmented CCL17, IL-1 receptor antagonist, and IL-10. We concluded that high-dose ARB inhibits glomerular inflammation by increasing the numbers of M2 macrophages and upregulation of anti-inflammatory cytokines and by suppressing M1 macrophage development with downregulation of M1-related proinflammatory cytokines.angiotensin II type 1 receptor blocker THE RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) is a coordinated hormonal cascade that controls cardiovascular, renal, and adrenal function by regulating body fluid and electrolyte balances as well as arterial pressure (2, 41). ANG II is the principal RAAS effector peptide, and, through its binding to the ANG II type 1 receptor (AT 1 R), ANG II mediates a range of actions, including vasoconstriction, aldosterone and vasopressin release, sodium and water retention, and sympathetic activation. These activities may in turn induce hemodynamic alterations and hypertension. In addition to its systemic hemodynamic effects, ANG II was recently reported to be associated with several pathophysiological actions that facilitate specific tissue and organ injuries, including the production of proinflammatory mediators, cell proliferation, extracellular matrix synthesis, and release of reactive oxygen species (40,42).AT 1 R blockade (ARB) selectively inhibits the binding of ANG II to AT 1 R, and recent evidence indicated a role for ARB

Shimizu A, Higo S, Fujita E, Mii A, Kaneko T. Focal segmental glomerulosclerosis after renal transplantation.
Clin Transplant 2011: 25 (Suppl. 23): 6–14.
© 2011 John Wiley & Sons A/S. Abstract:  Focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome of proteinuria, usually of nephrotic range, associated with focal and segmental sclerotic glomerular lesions. Therefore, FSGS is diagnosed by clinical features and histopathological examination of renal biopsy. The natural history of the condition varies, and although it may respond to treatment, FSGS is an important disease in the etiology of end‐stage renal disease (ESRD). Furthermore, after kidney transplantation, approximately 30% of patients with FSGS develop recurrent FSGS. The risk factors for recurrence of FSGS include childhood onset and age <15 yr, rapid progression of the primary FSGS to ESRD, recurrence of FSGS in a previous allograft, diffuse mesangial hypercellularity in the native kidney, collapsing FSGS, and podocin gene mutation. In addition, after kidney transplantation, de novo FSGS also develops in approximately 10–20% of allografts, associated with a complication of hyperfiltration injury, chronic transplant glomerulopathy, and calcineurin inhibitor toxicity. FSGS is considered a podocyte disease, and the pathology is characterized by segmental FSGS lesion with glomerular epithelial hypercellularity. The pathological diagnosis of FSGS is based on the 2004 Columbia classification system. In the present minireview, we discuss the pathology of recurrence and de novo FSGS after kidney transplantation.

Macrophages are heterogeneous and include classically activated M1 and alternatively activated M2 macrophages, characterized by pro-and anti-inflammatory functions, respectively. Macrophages that express heme oxygenase-1 also exhibit anti-inflammatory effects. We assessed the anti-inflammatory effects of statin in experimental anti-glomerular basement membrane glomerulonephritis and in vitro, focusing on the macrophage heterogeneity. Rats were induced anti-glomerular basement membrane glomerulonephritis and treated with atorvastatin (20 mg/kg/day) or vehicle (control). Control rats showed infiltration of macrophages in the glomeruli at day 3 and developed crescentic glomerulonephritis by day 7, together with increased mRNA levels of the M1 macrophage-associated cytokines, interferon-␥, tumor necrosis factor-␣, and interleukin-12.

Thrombotic microangiopathy (TMA) is a known complication of hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA is controversial but considered to involve various factors such as total body irradiation, use of calcineurin inhibitors for prophylaxis against graft versus host disease (GVHD), viral infection, and GVHD. Herein we describe a case with renal TMA after HSCT, which was probably associated with antibody-mediated endothelial cell injury from chronic GVHD (termed here 'chronic humoral GVHD'). A 49-year-old man presented two years after HSCT with renal dysfunction and proteinuria but without the clinical features of TMA. Histopathological examination of renal biopsy showed chronic glomerular endothelial cell injury with double contour of the glomerular basement membrane, microthrombi and the deposition of complement split product C4d along the glomerular capillaries. Renal tubulitis and peritubular capillaritis were also noted with a multilayered basement membrane and patchy C4d deposition on peritubular capillaries. These findings resemble those of chronic antibody-mediated rejection after kidney transplantation. Furthermore, C4d deposition suggests complement activation. Although circulating anti-blood type and anti-human leukocyte antigen antibodies were not detected, the renal TMA in this case was probably associated with chronic humoral GVHD.

During nephrogenesis, lymphatic vessels extend from the renal hilus into the renal cortex along the renal blood vasculature. Podoplanin, prox-1, Ki-67, type IV collagen, and αSMA immunostaining can detect lymphatic vessels during lymphangiogenesis.