R ecent data suggest that hypertension and hypertensive end-organ damage are not only mediated by hemodynamic injury but also by innate and adaptive immune responses. 1 In their seminal article, Guzik et al 2 were able to show that RAG-1 -/-mice that lack T and B cells have attenuated hypertension in response to angiotensin II (Ang II) infusion. This finding was confirmed in SCID mice. 3 In 2005, a novel T-helper cell subset (Th17) producing interleukin 17 (IL-17) was discovered.4 IL-17 is a proinflammatory cytokine secreted by innate and adaptive immune cells. Although the source of IL-17 is restricted to hematopoietic cells, the IL-17 receptor is widely expressed. Th17 cells need interleukin 23 (IL-23) for expansion and survival. IL-23 is secreted by activated dendritic cells and macrophages. The potential function of Th17 cells in autoimmune disease was first shown in IL-23p19-deficient mice. IL-23p19 knockout animals demonstrated a substantial decrease in Th17-polarized cells and were resistant to the development of experimental autoimmune encephalomyelitis, 5 experimental induction of multiple sclerosis, and rheumatoid arthritis. A new link between cardiovascular disease and IL-17 has been proposed by recent data showing that increased dietary salt intake drives autoimmune diseases through the induction of Th17 cells. C57black mice are resistant to hypertensive end-organ damage. 7 We recently showed that combining deoxycorticosterone acetate (DOCA) salt and Ang II infusion induces substantial hypertensive renal and cardiac injury. 8 This model has been successfully used to evaluate the role of chemokine receptors and ADMA (asymmetric dimethylarginine) in hypertensive end-organ damage.

Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.

5 alpha-Reductase deficiency is a rare autosomal recessive disorder of defective virilization in karyotypic males due to reduced conversion of testosterone to dihydrotestosterone. The gene encoding the affected 5 alpha-reductase type 2 enzyme has recently been cloned, and mutations within the coding region have been discovered as the cause of this disease. We address the possibility of a rapid nonradioactive molecular genetic screening technique for initial diagnosis and report different point mutations in this gene in eight unrelated patients with clinical features of 5 alpha-reductase deficiency. For molecular genetic analysis, DNA from peripheral blood leukocytes was studied. The coding region of the 5 alpha-reductase type 2 gene was characterized by exon-specific PCR amplification, nonradioactive single strand conformation analysis, and direct sequencing. In seven patients, homozygous point mutations were identified (Leu55-Gln, delta Met157, Gly196-Ser, Arg227-Gln, Ala228-Thr, and His231-Arg). One individual was a compound heterozygote carrier of two mutations (Ile112-Asn and Gln126-Arg). We conclude that molecular genetic characterization of point mutations in the 5 alpha-reductase type 2 gene may be used as an additional valuable procedure for the diagnosis of this disorder.

Certain germline mutations (607Arg-Gln, 608Arg-Lys) in the androgen receptor gene have been associated with the occurrence of breast cancer in males suffering from partial androgen insensitivity. To assess whether somatic mutations in this gene could be detected in breast carcinoma, archival tumor tissue of males without clinical evidence of androgen insensitivity was screened for point mutations in the androgen receptor gene. DNA was retrieved by chloroform-phenol extraction from formalin-fixed, paraffin-embedded tissues. Exons 2-8 of the androgen receptor gene, encoding the DNA- and hormone-binding regions of the receptor, were amplified by polymerase chain reaction and subjected to nonisotopic single strand conformation assay (SSCA) to screen for point mutations. In the tumor DNA, no variations suggestive of mutations were encountered on SSCA. However, in a control patient with partial androgen insensitivity and predominantly female phenotype, the germline mutation 607Arg-Gln was identified in blood leukocyte DNA. Our results indicate that somatic mutations of the androgen receptor are not required for the development of male breast cancer. This, however, does not exclude an increased risk of breast carcinoma in patients with androgen insensitivity.