Previous experimental data suggest that steroids might have protective effects during hypoxic/ischemic injury of various organs. In this study, the association between dexamethason (Dexa) treatment and the anti-apoptotic SGK-1 was tested in ischemic renal injury. In vitro, HK-2 cells were exposed to 24 h hypoxia, and the effect of Dexa incubation on SGK-1 expression / activation and on cell death was studied. In an in vivo rat model of unilateral renal IR, animals were treated with Dexa, and serum renal function parameters, tissue injury and SGK-1 expression and localization were examined after different reperfusion times (2 h, 4 h and 24 h). Dexa at a dose of 2 mg/L exerted a protective effect on cell survival assessed by LDH release and vital staining paralleled by marked up-regulation of SGK-1. In rats, 2 mg/kg Dexa treatment 24 h prior to ischemia resulted in less severe tissue injury and ameliorated urea nitrogen levels 24 h after reperfusion. Furthermore, SGK-1 expression and phosphorylation were higher in Dexa animals demonstrated by Western blot and immunofluorescence technique. Our results provide novel data on the signalling mechanism of Dexa under hypoxia / ischemia and further support that Dexa emerges as an attractive pharmacological agent for the prevention of ischemic injury.

The Department of Pathology and Laboratory Medicine offers a Ph.D. in Biomedical Sciences with a focus on Experimental Pathology. The graduate program emphasizes experimental approaches to better understand the molecular and cellular mechanisms of disease, particularly human disease. Principal areas of research investigated by faculty in Experimental Pathology include concentrating studies in microbial genomics, innate immunity, cellular stress, stem cell biology, developmental neurobiology, cancer, and neurodegenerative disease. The Department of Pathology & Laboratory Medicine offers a graduate program in Experimental Pathology. Application to Experimental Pathology is generally through one of two "gateway" programs, which offer multidisciplinary graduate training under the heading of Cellular and Molecular Biosciences (CMB) (https://cmb.uci.edu) or the Interdepartmental Neuroscience Program (INP) (https://inp.uci.edu). Members of the Pathology faculty participate in the CMB and INP programs. The CMB and INP programs include a first-year curriculum and the opportunity to rotate through two or more research laboratories. For the CMB program, students select a specific area of interest from ten areas of academic study, one of which is Experimental Pathology. Experimental Pathology emphasizes experimental approaches to better understand the molecular and cellular mechanisms of disease, with a focus on human disease. After the first year in the CMB or INP program, students interested in Experimental Pathology will join the laboratories of faculty within the department or the laboratories of approved affiliated faculty. Students end of third year. The normative time for completion of the Ph.D. is five years, and the maximum time permitted is seven years. immune evasion by cancer, diseases mediated by cytokine dysregulation, role of the microbiome of the GI tract and other disease sites, and adoptive T-cell therapy.

Introduction and Aims: Clinical studies have demonstrated the risk of chronic kidney disease after the occurrence of an acute kidney injury (AKI).Experimental works indicate that AKI result in incomplete repair, persistent tubulointerstitial inflammation and fibrosis.Cysteine-rich protein 61 (Cyr61), a secreted matrix-associated protein, has been found to be up-regulated in the kidney ischemia reperfusion injury (IRI) animal model.The present study aimed to investigate the role of Cyr61 in the kidney after IRI.Methods: Using mouse unilateral IRI model, we analyzed gene and protein expression of Cyr61.We further investigated the effect of blockade of Cyr61 in unilateral IRI mice by treating polyclonal anti-Cyr61 antibody or non-specific IgG.In addition, we used proximal tubular epithelial (NRK-52E) cells for cell culture studies.Results: After IRI, kidney Cyr61 expression increased significantly in both mRNA and protein level.Immunofluorescence staining indicated Cyr61 was predominantly expressed in renal proximal tubular epithelial cells.This was supported by in vitro studies showing hypoxia condition stimulate Cyr61 expression in NRK-52E cells.Daily treatment with anti-Cyr61 antibody produced a decrease in the renal type 1 collagen, PAI-1, MCP-1, and IL-1 gene expression, as well as α-SMA protein production at day 14 after IRI.The degree of collagen fibril accumulation, evaluated by picrosirius red staining, and macrophage infiltration were both attenuated by the Cyr61 blockade on day 7 and 14.Concurrently, renal VEGF-A gene expression was enhanced and vessel density was more preserved at day 14 in the treatment group.Conclusions: Renal Cyr61 expression by tubular epithelial cells is enhanced after IRI.Our findings suggest that Cyr61 contributes to the renal inflammation, vascular rarefaction, and fibrosis after ischemic AKI.

Solid-organ transplantation is the optimal long-term treatment for most patients with end-stage organ failure. After solid-organ transplantation, short-term graft survival significantly improved (1). However, due to chronic allograft nephropathy and death with functioning graft, long-term survival has not prolonged remarkably (2). Posttransplant immunosuppressive medications consist of one of the calcineurin inhibitors in combination with mycophenolate mofetil (MMF) or azathioprine (Aza) and steroids. All of them have different adverse effects, among which posttransplant diabetes mellitus (PTDM) is an independent risk factor for cardiovascular (CV) events and infections causing the death of many transplant patients and it may directly contribute to graft failure (3). According to the criteria of the American Diabetes Association (4), diabetes mellitus (DM) is defined by symptoms of diabetes (polyuria and polydipsia and weight loss) plus casual plasma glucose concentration ≥ 11.1 mmol/L or fasting plasma glucose (FPG) ≥ 7.0 mmol/L or 2-h plasma glucose level ≥ 11.1 mmol/L following oral glucose tolerance test (OGTT). This metabolic disorder occurring as a complication of organ transplantation has been recognized for many years. PTDM, which is a combination of decreased insulin secretion and increased insulin resistance, develops in 4.9/15.9% of liver transplant patients, in 4.7/11.5% of kidney recipients, and in 15/17.5% of heart and lung transplants [cyclosporine A (CyA)/tacrolimus (Tac)-based regimen, respectively] (5). Risk factors of PTDM can be divided into non-modifiable and modifiable ones (6), among which the most prominent is the immunosuppressive therapy being responsible for 74% of PTDM development (7). Emphasizing the importance of the PTDM, numerous studies have determined the long-term outcome. On the basis of these studies, graft and patient survival is tendentiously (8) or significantly (9, 10) decreased for those developing PTDM.

The novel metabolic receptor GPR91 controls renin release, the rate-limiting step of RAS, and the renal collecting duct (CD) is the major source of (pro)renin in diabetes. Since the highest GPR91 expression was found in the CD, this study investigated whether succinate, the ligand of GPR91 regulates the local CD RAS. Western blot analysis of succinate-treated M1 cells (CD cell line) showed a dose-dependent, 2–2.5-fold elevation in pERK½, pp38, COX2, renin, prorenin and its receptor [(P)RR]. In WT and GPR91−/− control and STZ-diabetic (DM) mice, CD pERK1/2 (by immunofluorescence) and urinary PGE2 excretion (measured by ELISA) increased 4–20 fold in DM mice and were GPR91-dependent. Medullary (pro)renin and (P)RR protein expression (by immunoblotting) and renin activity in the CD tubular fluid (visualized in vivo using multiphoton microscopy and a fluorogenic renin substrate delivered by renal micropuncture) increased 4–5 fold in WT DM vs. control mice, which was completely abolished in GPR91−/− DM mice. This is the first, direct demonstration of CD renin activity in vivo. Succinate accumulation and GPR91 signaling are novel (patho)physiological regulatory mechanisms that activate the local RAS in the CD via MAP kinases and COX2, PGE2 release, and increased (pro)renin and (P)RR synthesis. Succinate and GPR91 may be important regulators of the local CD RAS in DM and new therapeutic targets in diabetic nephropathy. Supported by: DK74754 and University Kidney Research Organization.

Background. Anatomical malformations of the kidney and urinary tract account for 17% of pediatric renal transplantation procedures. Heat shock proteins (HSPs) are molecular chaperones with a protective function that promotes cell survival. HSP72 is an endogenous ligand for toll-like receptor TLR4, thereby stimulating innate immunity. Both in adults and children, decreased expression of HSP70s is associated with a number of kidney diseases.Objective. To assess the prevalence of HSPA1A G(190)C, HSPA1B A(1267)G, and TLR4 A(896)G polymorphisms in children who had undergone kidney transplantation. Patients and Methods. Genotypes were analyzed using allele-specific polymerase chain reaction in 41 pediatric recipients. Allelic prevalence was related to reference values in 65 age- and sex-matched healthy children.Results. Clinical data did not reveal a difference between any of the groups. HSPA1B (1267)GG genotype and HSPA1B (1267)G allele were observed more frequently in the transplant recipients compared with the control group: AA vs AG: odds ratio [OR], 12.6; 95% confidence interval [CI], 1.58-100.0; P = .004; AA vs GG: OR, 20.80; 95% CI, 2.32-187.00; P = .01; and A vs G: OR, 2.10; 95% CI, 1.19-3.07; P = .01. Furthermore, the prevalence of the HSPAIB (1267)GG genotype was greater in transplant recipients with vs without urinary tract malformations: AG vs GG: OR, 0.10; 95% CI, 0.09-0.48; P = .007. No differences were observed in the other studied polymorphisms.Conclusion. Our findings suggest an association between the carrier status of HSPA1B (1267)G with urinary tract malformations, leading to end-stage renal disease requiring kidney transplantation. This observation raises further questions about the clinical and therapeutic relevance of this polymorphism to pediatric nephrology.