Circulating microRNAs associate with diabetic nephropathy and systemic microvascular damage and normalize after simultaneous pancreas-kidney transplantation.

Because microvascular disease is one of the most important drivers of diabetic complications, early monitoring of microvascular integrity may be of clinical value. By assessing profiles of circulating microRNAs (miRNAs), known regulators of microvascular pathophysiology, in healthy controls and diabetic nephropathy (DN) patients before and after simultaneous pancreas-kidney transplantation (SPK), we aimed to identify differentially expressed miRNAs that associate with microvascular impairment. Following a pilot study, we selected 13 candidate miRNAs and determined their circulating levels in DN (n = 21), SPK-patients (n = 37), healthy controls (n = 19), type 1 diabetes mellitus patients (n = 15) and DN patients with a kidney transplant (n = 15). For validation of selected miRNAs, 14 DN patients were studied longitudinally up to 12 months after SPK. We demonstrated a direct association of miR-25, -27a, -126, -130b, -132, -152, -181a, -223, -320, -326, -340, -574-3p and -660 with DN. Of those, miR-25, -27a, -130b, -132, -152, -320, -326, -340, -574-3p and -660 normalized after SPK. Importantly, circulating levels of some of these miRNAs tightly associate with microvascular impairment as they relate to aberrant capillary tortuosity, angiopoietin-2/angiopoietin-1 ratios, circulating levels of soluble-thrombomodulin and insulin-like growth factor. Taken together, circulating miRNA profiles associate with DN and systemic microvascular damage, and might serve to identify individuals at risk of experiencing microvascular complications, as well as give insight into underlying pathologies.

Erythropoietin, progenitors, and repair.

The erythropoietin-erythropoietin-receptor (EPO-EPO-R) system has recently been identified as an important cellular survival pathway. Its presence has also been demonstrated in the kidney and identified as a therapeutic target to prevent loss of renal function. Part of the protective effects may be related to the action of erythropoietin on endothelial function and expansion of endothelial progenitor cells. This paper reviews current evidence for involvement of these mechanisms in EPO-mediated renoprotection.

Anti-C1q autoantibodies in murine lupus nephritis.

Autoantibodies against C1q can be found in the circulation of patients with several autoimmune diseases including systemic lupus erythematosus (SLE). In SLE there is an association between the occurrence of these antibodies and renal involvement. How anti-C1q autoantibodies contribute to renal disease is currently unknown. Cohorts of MRL-lpr mice, which are known to develop age-dependent SLE-like disease, were used to study the relationship between levels of anti-C1q autoantibodies and renal disease. We collected serum, urine and renal tissue and analysed autoantibodies, complement levels and renal deposition as well as renal function. At 2 months of age all mice already had elevated levels of anti-C1q autoantibodies, and elution of kidneys revealed the presence of these antibodies in renal immune deposits in MRL-lpr mice and not in control MRL+/+ mice. In conclusion, anti-C1q antibodies are already present in serum and immune deposits of the kidney early in life and therefore can play a role in nephritis during experimental SLE-like disease in mice.

Immune deposition of C1q and anti-C1q antibodies in the kidney is dependent on the presence of glomerular IgG.

Anti-C1q autoantibodies are found frequently in patients with Systemic Lupus Erythematosus (SLE) and several studies indicate that these autoantibodies are associated with renal involvement. We have shown earlier that administration of anti-C1q antibodies to normal BALB/c mice results in the deposition of these antibodies and C1q in the kidney. In the present study we have investigated which factors are essential for this C1q-anti-C1q deposition. Injection of anti-C1q antibodies in C57BL/6 mice results in deposition of both C1q and anti-C1q in glomeruli, while administration of equal concentrations of anti-C1q to immunoglobulin deficient Rag2-/- mice did not result in deposition of anti-C1q antibodies. Analysis of renal sections of naive Rag2-/- mice revealed absence of mouse IgG and C1q in the glomeruli, while circulating C1q was within normal levels. Reconstitution of Rag2-/- mice with IgG, either by injection with purified mouse IgG or by splenocyte transfer, resulted in restored localization of mouse IgG together with C1q in the kidney. Subsequent injection of anti-C1q antibodies in these IgG reconstituted mice resulted in clear deposition of C1q together with anti-C1q in the kidneys comparable to that found in C57BL/6 mice receiving anti-C1q. We propose that the continuous presence of serum derived non-immune IgG in the glomerulus serves as a target for low affinity interactions with C1q, which then can serve as antigen for anti-C1q antibodies. Therefore we hypothesize that high and fluctuating levels of IgG as observed in patients with SLE may contribute to flares of renal inflammation in those patients with anti-C1q autoantibodies.

Glomerular deposition of C1q and anti-C1q antibodies in mice following injection of antimouse C1q antibodies.

Anti-C1q autoantibodies are present in the serum of patients with different autoimmune diseases such as systemic lupus erythematosus (SLE). The occurrence of these autoantibodies correlates with renal involvement. In the present study we examined whether injection of rabbit antimouse C1q antibodies in mice leads to deposition in kidneys. Injection of healthy mice with a single dose of rabbit IgG antimouse C1q antibodies resulted in deposition of both C1q and IgG anti-C1q in glomeruli. The pattern of deposition observed in the glomeruli of mice injected with antimouse C1q antibodies both at 24 h and 2 weeks was both glomerular basement membrane (GBM)-associated and mesangial. Injection of control IgG did not have a detectable effect on circulating C1q levels, and no deposition of either C1q or rabbit IgG was seen at 24 h. The deposition of rabbit antimouse C1q and C1q in glomeruli resulted in complement activation, as assessed by C3 deposition, and influx of leucocytes associated with albuminuria in some, but not all mice. In none of the control mice was albuminuria observed. This report is the first to show that anti-C1q antibodies deposit in the healthy glomerulus together with autologous C1q. This deposition is stable for at least 2 weeks, causes complement activation, leucocyte influx and can lead to mild albuminuria.

Activity of human IgG and IgA subclasses in immune defense against Neisseria meningitidis serogroup B.

Both IgG and IgA Abs have been implicated in host defense against bacterial infections, although their relative contributions remain unclear. We generated a unique panel of human chimeric Abs of all human IgG and IgA subclasses with identical V genes against porin A, a major subcapsular protein Ag of Neisseria meningitidis and a vaccine candidate. Chimeric Abs were produced in baby hamster kidney cells, and IgA-producing clones were cotransfected with human J chain and/or human secretory component. Although IgG (isotypes IgG1-3) mediated efficient complement-dependent lysis, IgA was unable to. However, IgA proved equally active to IgG in stimulating polymorphonuclear leukocyte respiratory burst. Remarkably, although porin-specific monomeric, dimeric, and polymeric IgA triggered efficient phagocytosis, secretory IgA did not. These studies reveal unique and nonoverlapping roles for IgG and IgA Abs in defense against meningococcal infections.