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.
Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken betaactin promoter. Mice were backcrossed in the C57Bl/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25-to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.
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