Inflammation has been established to contribute substantially to the pathogenesis of ischemia/reperfusion (I/R) with a central role for particular cells, adhesion molecules, and cytokines. Until recently, most of the research trying to unravel the pathogenesis of I/R injury has been focused on the role of neutrophils. However, recent studies have brought evidence that T cells and macrophages are also important leukocyte mediators of renal and extrarenal (liver) I/R injury. In vivo depletion of CD4+ cells but not CD8+ cells in wild-type mice was protective in I/R of the kidney. A marked preservation of liver function was also found after I/R in T-cell deficient athymic mice. Blocking the b130/CD28 costimulatory pathway by CTLA-4 Ig (recombinant fusion protein) ameliorated renal dysfunction and decreased mononuclear cell infiltration in I/R of the kidney. b130-1 expression was found limited to the membrane of the endothelial cells of the ascending vasa recta, resulting in trapping of CD28-expressing CD4 T cells. This trapping of leukocytes results in the upstream congestion in the ascending arterial vasa recta, generating the since more than 150 years described medullary vascular congestion of the kidney soon after ischemic injury. It seems worthwhile to study a combination therapy using anti-inflammatory/anti-adhesion molecules in the early phase of I/R.

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase which modulates the function of its substrates, among which are insulin-releasing incretins. DPP4 inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. Inhibition of DPP4 exhibits protective effects on ischemia-reperfusion injury (IRI) of the heart and lung. As DPP4 and its substrates are also expressed in the kidney, we studied the effect of the DPP4 inhibitor vildagliptin on the outcome of IRI-induced acute kidney injury in rats in a model of 30-min unilateral renal ischemia, followed by contralateral nephrectomy. Saline, 1, or 10 mg/kg vildagliptin (VG1/VG10) was administered intravenously 15 min before the surgery. Animals were euthanized after 2, 12, amd 48 h of reperfusion. DPP4 inhibition resulted in a significant dose-dependent decrease in serum creatinine (1.31 ± 0.32 and 0.70 ± 0.19 mg/dl for VG1 and VG10, respectively, vs. 1.91 ± 0.28 mg/dl for controls at 12 h; P < 0.01). Tubular morphology (PAS-PCNA) revealed significantly reduced tubular necrosis at 12 h (62.1 ± 18.0 and 77.5 ± 22.0% in VG10 and saline, respectively). VG did not affect regeneration but decreased apoptosis, as shown by twofold decreased Bax/Bcl-2 mRNA expression and a threefold decrease in apoptotic bodies on terminal deoxynucleotidyl transferase dUTP nick-end labeling-stained sections. VG treatment significantly reduced serum malondialdehyde twofold in both VG1- and VG10-treated ischemic and sham-operated animals compared with controls and also resulted in a significant decrease in mRNA expression of the proinflammatory marker CXCL10 at 2 h of reperfusion. Through a mechanism yet to be fully understood, VG treatment results in a functional protection of the kidney against IRI. This protection was associated with antiapoptotic, immunological, and antioxidative changes.

Erythropoietin (EPO) exerts (renal) tissue protective effects. Since it is unclear whether this is a direct effect of EPO on the kidney or not, we investigated whether EPO is able to protect human renal tubular epithelial cells (hTECs) from oxidative stress and if so which pathways are involved. EPO (epoetin delta) could protect hTECs against oxidative stress by a dose-dependent inhibition of reactive oxygen species formation. This protective effect is possibly related to the membranous expression of the EPO receptor (EPOR) since our data point to the membranous EPOR expression as a prerequisite for this protective effect. Oxidative stress reduction went along with the upregulation of renoprotective genes. Whilst three of these, heme oxygenase-1 (HO-1), aquaporin-1 (AQP-1), and B-cell CLL/lymphoma 2 (Bcl-2) have already been associated with EPO-induced renoprotection, this study for the first time suggests carboxypeptidase M (CPM), dipeptidyl peptidase IV (DPPIV), and cytoglobin (Cygb) to play a role in this process.

Background/Aims: The present study was conducted to investigate the renal tubular handling of inorganic cadmium (Cd²⁺) by exposing primary human tubular cell cultures to physiologically relevant doses of cadmium chloride (CdCl₂). Furthermore, the cellular accumulation of Cd²⁺ was compared to that of metallothionein-1-bound Cd (Cd7MT-1). Finally, this study aimed to investigate the effect of the accumulation of Cd (both Cd²⁺ and Cd7MT-1) in renal cells on the expression of genes relevant to nephrotoxic processes. Methods: Cd concentration was measured using atomic absorption spectrometry. mRNA expression was evaluated by quantitative real-time RT-PCR. Results: Cd²⁺ accumulated into human tubular cells in a concentration- and time-dependent way. Furthermore, cellular accumulation of Cd²⁺ was different from the cellular accumulation of Cd7MT-1, indicative for different uptake routes. Finally, mRNA expression of the genes encoding the anti-oxidative proteins metallothionein-1 (MT-1) and heme-oxygenase-1 (HO-1) as well as the pro-apoptotic Bcl-2-associated X protein (Bax) were upregulated by CdCl₂ and not by Cd7MT1. Conclusion: In the presence of physiologically relevant Cd concentrations, tubular accumulation of the element in its inorganic form is different from that of Cd7MT-1. Furthermore, the tubular accumulation of inorganic Cd induces mRNA expression of genes of which the protein products may play a role in Cd-associated renal toxicity.

Erythropoietin (EPO) has been shown to have tissue protective properties by binding to its receptor (EPOR) which is also expressed on non-haematopoietic cells. The mechanisms underlying this protection have not yet been elucidated and the renal cell types mediating these effects remain ill-defined. This study aimed to identify the EPOR expression in human tubular epithelial cells (hTECs) and in rat kidney and to investigate the role of EPOR in EPO-mediated renoprotection. Male Wistar rats were treated with saline or EPO (3000 U/kg, i.p.) 24h prior to sham-operation or 30 min bilateral renal ischemia. Renal morphology and function, tubular regeneration, apoptosis and expression of EPOR, hemeoxygenase-1 (HO-1) and hepatocyte growth factor (HGF) were analyzed. Primary cultures of human proximal (PTC) and distal/collecting duct (DTC) tubular cells were incubated with EPO (5-50-500 ng/mL) either or not in the presence of soluble EPOR. Total RNA was extracted and mRNA expression of HO-1 was investigated by quantitative RT-PCR. EPOR mRNA could be demonstrated in hTECs and in cortical tubules of the rat kidney. Furthermore, EPOR protein was expressed at the membrane and as intracellular vesicles in hTECs. In vivo, EPO treatment attenuated histological and functional renal damage, decreased both cell necrosis and apoptotic cell death, enhanced tubular regeneration and resulted in an upregulation of HO-1 and HGF mRNA. In vitro, EPO administration resulted in an early upregulation of HO-1 mRNA which was restricted to PTC and inhibited by simultaneous addition of supra-equivalent amounts of soluble EPOR. These data strongly suggest that the EPO-mediated renoprotection results from direct interaction of EPO with EPOR on tubular cells.