Glomerulonephritis (GN) isM esenchymal stem cells (MSC) hold special promise for renal repair, because nephrons are largely of mesenchymal origin (1). The potential of MSC for renal repair has been shown in rodent models of acute renal failure (ARF), where the course of glycerol, cisplatin, or ischemia-reperfusion induced ARF was improved by MSC injection shortly after disease induction (2-5). In addition, we recently reported that injection of rat MSC into a renal artery can accelerate recovery from mesangiolytic damage and prevent transient ARF in rat anti-Thy1.1 glomerulonephritis (GN) (6). AntiThy1.1 nephritis is a model of acute mesangioproliferative glomerulonephritis and is characterized by initial mesangiolysis followed within a few days by glomerular repair via endothelial and mesangial cell proliferation and accumulation of mesangial matrix. We have also provided evidence that MSC likely exerted these effects in glomeruli by paracrine effects, such as the release of high amounts of vascular endothelial growth factor (VEGF) and TGF-␤1 rather than by differentiation into resident glomerular cell types or monocytes/macrophages (6).In this study, we investigated the long-term effects of MSC administration in early anti-Thy1.1 nephritis. Normally, antiThy1.1 nephritis in rats follows a self-limited course, and spontaneous restitution of the glomerular architecture can be observed within approximately 4 wk. For enhancement of the relevance of the model for progressive renal disease in humans, the model in this study was aggravated and transformed into a course of progressive renal failure by previous uninephrectomy of the rats (7,8). Materials and MethodsRats were housed under standard conditions in a light-, temperature-, and humidity-controlled environment with free access to tap water and standard rat diet. All animal protocols were approved by the local government authorities. Harvest and Culture of MSCInbred male Lewis rats that weighed 180 to 210 g (Harlan, Horst, Netherlands) served as bone marrow donors; MSC were prepared as described previously (6). Cells were seeded onto six-well plates (nine

No abstract

Mesenchymal stem cell (MSC) transplantation has the potential for organ repair. Nevertheless, some factors might lessen the regenerative potential of MSCs, e.g. donor age or systemic disease. It is thus important to carefully assess the patient's suitability for autologous MSC transplantation. Here we investigated the effects of chronic kidney disease (CKD) on MSC function. We isolated bone marrow MSCs from remnant kidney rats (RK) with CKD (CKD-RK-MSC) and found signs of premature senescence: spontaneous adipogenesis, reduced proliferation capacity, active senescence-associated-β-galactosidase, accumulation of actin and a modulated secretion profile. The functionality of CKD-RK-MSCs in vivo was tested in rats with acute anti-Thy1.1-nephritis, where healthy MSCs have been shown to be beneficial. Rats received healthy MSCs, CKD-RK-MSC or medium by injection into the left renal artery. Kidneys receiving healthy MSCs exhibited accelerated healing of glomerular lesions, whereas CKD-RK-MSC or medium exerted no benefit. The negative influence of advanced CKD/uremia on MSCs was confirmed in a second model of CKD, adenine nephropathy (AD). MSCs from rats with adenine nephropathy (CKD-AD-MSC) also exhibited cellular modifications and functional deficits in vivo. We conclude that CKD leads to a sustained loss of in vitro and in vivo functionality in MSCs, possibly due to premature cellular senescence. Considering autologous MSC therapy in human renal disease, studies identifying uremia-associated mechanisms that account for altered MSC function are urgently needed.

In vitro studies identified Y-box–binding protein (YB)-1 as a key regulator of inflammatory mediators. In this study, we observed increased levels of secreted YB-1 in sera from sepsis patients. This led us to investigate the in vivo role of YB-1 in murine models of acute peritonitis following LPS injection, in sterile renal inflammation following unilateral ureteral obstruction, and in experimental pyelonephritis. LPS injection enhanced de novo secretion of YB-1 into the urine and the peritoneal fluid of LPS-treated mice. Furthermore, we could demonstrate a significant, transient upregulation and posttranslational modification (phosphorylation at serine 102) of YB-1 in renal and inflammatory cells. Increased renal cytoplasmic YB-1 amounts conferred enhanced expression of proinflammatory chemokines CCL2 and CCL5. Along these lines, heterozygous YB-1 knockout mice (YB-1+/d) that display 50% reduced YB-1 levels developed significantly lower responses to both LPS and sterile inflammation induced by unilateral ureteral obstruction. This included diminished immune cell numbers due to impaired migration propensities and reduced chemokine expression. YB-1+/d mice were protected from LPS-associated mortality (20% mortality on day 3 versus 80% in wild-type controls); however, immunosuppression in YB-1+/d animals resulted in 50% mortality. In conclusion, our findings identify YB-1 as a major, nonredundant mediator in both systemic and local inflammatory responses.