Improving the ability of the kidney to tolerate ischemic injury has important implications. We investigated the effect of recombinant human erythropoietin (rHuEPO) treatment on subsequent ischemia/reperfusion (I/R) injury and evaluated the role of heat shock protein (HSP) 70 in rHuEPO-induced renal protection. rHuEPO (3000 U/kg) was administered 24 h before I/R injury, and rats were killed at 24, 48, and 72 h after I/R injury. Pretreatment of rHuEPO resulted in the following: i) decreased serum creatinine level; ii) decreased tubular cell apoptosis and necrosis, measured by DNA fragmentation analysis and TUNEL staining and histomorphological criteria; iii) decreased tubular cell proliferation as determined by proliferating cell nuclear antigen expression; iv) increased bcl-2 protein and decreased caspase 3 activity; and v) decreased JNK expression. rHuEPO treatment increased HSP70 expression in a dose-dependent manner in normal rat kidneys, and inhibition of HSP70 expression by quercetin eliminated the renoprotective effect of rHuEPO in ischemic kidneys. Our study demonstrates that rHuEPO has a protective effect on subsequent I/R injury and that this effect is associated with induction of HSP70. Our study provides a new avenue for therapy to prevent renal damage after I/R injury.

I/R injury rapidly activates the innate immune response.

We report here our 10-year experience of a biopsy performed at day 14 after transplantation in 304 patients with stable graft function. The factors that may have influenced subclinical rejection were analyzed according to histology. The incidence of subclinical rejection was 13.2%. Addition of mycophenolate mofetile (MMF) as a primary immunosuppressant significantly decreased the incidence of subclinical rejection compared with patients without such treatment (odds ratio, 0.23; p < 0.05). On the other hand, HLA-DR antigen mismatch (odds ratio, 2.39) and unrelated donor (odds ratio, 2.10) were also significantly associated with decreased subclinical rejection (p < 0.05). The incidence of acute rejection in patients with normal findings was lower than in those with borderline changes or subclinical rejection (0.23 ± 0.05 vs. 0.48 ± 0.07 and 0.60 ± 0.11, respectively; p < 0.05). The graft survival rates in patients with subclinical rejection were lower than in patients with normal or borderline changes at 1 (88.4% vs. 97.9% and 99.1%; p < 0.05), 5 (77.8% vs. 96.2% and 95.9%; p < 0.05) and 10 (62.3% vs. 96.2% and 93.7%; p < 0.05) years. Thus, a protocol biopsy performed on day 14 after transplantation is useful for predicting graft survival. Triple therapy including MMF, related donor and HLA-DR antigen match are important factors for reducing subclinical rejection in living-donor renal transplantation.

Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA.

Peroxisome proliferator-activated receptor (PPAR)␣, a member of the ligand-activated nuclear receptor superfamily, plays an important role in lipid metabolism and glucose homeostasis and is highly expressed in the kidney. The present studies were aimed at determining the role of PPAR␣ in the pathogenesis of diabetic nephropathy using PPAR␣-knockout mice and cultured murine mesangial cells. Diabetes was induced using a low-dose streptozotocin protocol in 8-week-old male 129 SvJ PPAR␣-knockout and wild-type mice. Diabetic PPAR␣-knockout and wildtype mice developed elevated fasting blood glucose (P < 0.001) and HbA 1c levels (P < 0.001). Renal functional and histopathological changes in diabetic and nondiabetic PPAR␣-knockout and wild-type mice were evaluated after 16 weeks of hyperglycemia. PPAR␣ immunostaining of the cortical tubules of diabetic wild-type mice was elevated by hyperglycemia. In diabetic PPAR␣-knockout mice, renal disease with accompanying albuminuria, glomerular sclerosis, and mesangial area expansion was more severe than in diabetic wild-type mice (P < 0.05) and was accompanied by increased levels of serum free fatty acids and triglycerides (P < 0.01). Furthermore, they exhibited increased renal immunostaining for type IV collagen and osteopontin, which was associated with increased macrophage infiltration and glomerular apoptosis. There were no significant differences in these indexes of renal disease between nondiabetic PPAR␣-knockout and wild-type mice and diabetic PPAR␣ wild-type mice. In vitro studies demonstrated that high glucose levels markedly increased the expression of type IV collagen, transforming growth factor-␤1, and the number of leukocytes adherent to cultured mesangial cells. Adherence of leukocytes was inhibited by the PPAR␣ agonist fenofibrate. Taken together, PPAR␣ deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating free fatty acid and triglyceride concentrations. PPAR␣ agonists may serve as useful therapeutic agents for type 1 diabetic nephropathy. Diabetes 55: [885][886][887][888][889][890][891][892][893] 2006

We investigated the effects of pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, on interstitial inflammation and fibrosis, using an animal model of chronic cyclosporine A (CsA)-induced nephropathy. Sprague-Dawley rats were maintained on a low-salt diet (0.05% sodium) and treated daily for 1 or 4 wk with vehicle (olive oil; 1 ml/kg sc), CsA (15 mg/kg sc), or both CsA and pravastatin (5 or 20 mg/kg in the drinking water). Anti-inflammatory and antifibrotic effects of pravastatin were studied by evaluating the concentrations of the inflammatory mediators osteopontin (OPN) and C-reactive protein (CRP), of fibrotic cytokine-transforming growth factor (TGF)-beta1, and the presence of ED-1-positive cells (macrophages). In addition, renal function, serum lipid levels, histopathology (arteriolopathy and tubulointerstitial fibrosis), and the expression of the vasoactive factors endothelial nitric oxide synthase (eNOS) and renin protein were also compared for different treatment groups. Pravastatin induced dose-dependent decreases in the expression of OPN, intrarenal CRP, and TGF-beta1, and in the numbers of ED-1-positive cells at 1 and 4 wk. These were accompanied by a significant attenuation of tubulointerstitial fibrosis at 4 wk. The downregulation of eNOS protein expression in CsA-treated rat kidney was markedly upregulated by pravastatin treatment, although intrarenal renin expression was unaffected. Renal dysfunction induced by CsA significantly improved with administration of pravastatin at a dose of 20 mg/kg. Neither CsA nor pravastatin influenced serum lipid or high-sensitivity CRP levels in the treatment groups. Thus in chronic CsA nephropathy, pravastatin effectively abrogates the progression of tubulointerstitial inflammation and fibrosis. This may support the clinical use of pravastatin.

Mammalian members of the forkhead box protein O (FoxO) class of transcription factors are implicated in the regulation of oxidative stress, and FoxO proteins are negatively regulated by the phosphatidylinositol 3-kinase (PI3K)–AKT signaling pathway. We examined the effect of Klotho on the PI3K/AKT pathway and manganese superoxide dismutase (MnSOD) during tacrolimus (Tac)-induced oxidative stress. Klotho-treated mice showed decreased Tac-induced oxidative stress accompanied by functional and histological improvements. Klotho inhibited the PI3K/AKT-mediated phosphorylation of FoxO3a and enhanced FoxO3a binding to the MnSOD promoter. Klotho increased MnSOD mRNA and protein expression in mitochondria. In addition, Klotho reduced Tac-induced mitochondrial dysfunction and decreased mitochondrial reactive oxygen species production, and these effects were enhanced by blocking PI3K activity with LY294002. Collectively, our data showed that Klotho protects Tac-induced oxidative stress by negatively regulating the PI3K/AKT pathway and subsequently enhancing FoxO3a-mediated MnSOD expression.

Despite improvements in immunosuppressive therapy, long-term allograft survival after kidney transplantation remains as low as 50%. Chronic allograft nephropathy (CAN) is a major cause of late graft loss in renal transplant recipients. The histopathologic signs of CAN-interstitial fibrosis, tubular atrophy, glomerulopathy and vasculopathy-are nonspecific; therefore, the 2007 Banff classification dispensed with the term CAN in favor of 'interstitial fibrosis and tubular atrophy without evidence of any specific etiology'. In this Review, however, the term CAN is used to describe a clinical syndrome that is characterized by progressive decline in renal function from 3 months after transplantation, accompanied by the development of proteinuria and hypertension. The pathogenesis of CAN is complex and incompletely understood, and involves several immunological and non-immunological factors. We discuss the contributory roles of acute rejection, donor age, anti-human-leukocyte-antigen antibodies, calcineurin inhibitor nephrotoxic effects, viral infection, hypertension and hyperlipidemia. The prevention and treatment of CAN needs multidisciplinary strategies. Early detection by means of protocol biopsy and calculation of glomerular filtration rate is the first step, followed by management of modifiable risk factors.