Evidence that was obtained in several experimental models and in strains of hypertensive rats indicates that infiltration of inflammatory cells and oxidative stress in the kidney play a role in the induction and maintenance of hypertension. Similar evidence is lacking in human hypertension, at least in part, because immunosuppressive treatment is unjustified in patients with hypertension. For addressing this issue, patients who were prescribed by their private physicians mycophenolate mofetil (MMF) for the treatment of psoriasis or rheumatoid arthritis and had, in addition, grade I essential hypertension and normal renal function were studied. Eight patients were studied before MMF was started, during MMF treatment, and 1 mo after MMF treatment had been discontinued. Other treatments and diet were unchanged in the three phases of the study. MMF therapy was associated with a significant reduction in systolic, diastolic, and mean BP. Urinary excretion of TNF-α was reduced progressively by MMF treatment and increased after MMF was discontinued. Reduction of urinary malondialdehyde, TNF-α, and RANTES excretion during MMF administration did not reach statistical significance but had a direct positive correlation with the BP levels. These data are consistent with the hypothesis that renal immune cell infiltration and oxidative stress play a role in human hypertension.

Compelling evidence has emerged pointing to the interaction of oxidative stress and renal interstitial inflammation and their mutual contribution to the pathogenesis of hypertension in experimental animals. Renal interstitial inflammation in spontaneously hypertensive rats (SHR) is accompanied by and largely due to activation of redox-sensitive, proinflammatory nuclear transcription factor-κB (NF-κB). Therefore, the present study was designed to test the hypothesis that long-term inhibition of NF-κB, beginning early in the course of the disease, may attenuate renal interstitial inflammation and hypertension in SHR. To this end, we administered the reputed NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) (100 mg/kg daily intraperitoneally) to SHR from 7 to 25 weeks of age and compared the results with vehicle-treated SHR. Vehicle-treated and PDTC-treated Wistar Kyoto (WKY) rats served as controls. The untreated SHR exhibited a significant rise in arterial pressure; increased NF-κB activation, elevated intercellular adhesion molecule (ICAM)-1 and in situ mRNA macrophage chemoattractant molecule-1 (MCP-1) expressions; and interstitial accumulation of lymphocytes, macrophages, and angiotensin-II-positive cells. PDTC administration prevented the rise in blood pressure, and normalized renal cortical NF-κB activity as well as ICAM-1 and MCP-1 expressions. This was accompanied by a significant reduction in infiltration of immune cells, angiotensin II-expressing cells, and renal tissue malondialdehyde content to values that matched those found in the control WKY rats. Results suggest that NF-κB-driven intrarenal inflammatory reactivity play a major role in the pathogenesis of hypertension in the SHR.

Lymphocytes and macrophages infiltrate the kidney of spontaneously hypertensive rats (SHR) and interventions leading to their reduction are associated with improvement of the hypertension. The present studies examined the evolution of the interstitial inflammation in the natural course of the SHR to gain insight on the potential role of interstitial immune cell accumulation in the development of hypertension. We studied SHR and control WKY rats at 3 weeks (SHR-3wk group, n = 11 and WKY-3wk group, n = 10), 11 weeks (SHR-11wk group, n = 5 and WKY-11wk group, n = 5) and 24 weeks (SHR-24wk group, n = 10 and WKY-24wk group, n = 10). The SHR-3wk group was normotensive and older SHR developed hypertension that was severe in the SHR-24wk group. Tubulointerstitial accumulation of lymphocytes, macrophages, angiotensin II-positive cells, cells expressing the p65 DNA-binding subunit of NF-ĸB and activation of NF-ĸB in the kidney were all significantly increased (p < 0.01) in the prehypertensive SHR-3wk group and augmented progressively, with the highest values in the SHR-24wk group. The SHR-24wk group showed increased (p < 0.001) helper (CD4) T cell infiltration and a high CD4/CD8 ratio. These findings are consistent with the possibility that activation of NF-ĸB and renal interstitial infiltration of immune cells may be part of the pathophysiologic process that drives hypertension in the SHR.

Hypertension affects one-third of the adult population of the world. The causes of hypertension are incompletely understood, but relative impairment of sodium excretion is central to its pathogenesis. Immune cell infiltration in the kidney is a constant finding in hypertension that in association with local angiotensin and oxidants causes a defect in sodium excretion. However, it is unclear if the T cell influx into the kidney responds to nonspecific chemokine cues or is due to antigen-driven immune attraction. We found that T cells in experimentally induced salt-driven hypertension present a CD4 clonal response to heat shock protein 70 (HSP70) that is overexpressed in the kidney. We used a highly preserved amino acid sequence within the HSP molecule to induce immune tolerance associated with the generation of IL-10 producing regulatory T cells. Immune tolerant rats to HSP70 developed minimal renal inflammation and were protected from the development of salt-sensitive hypertension. Adoptive transfer of T lymphocytes isolated from spleen of tolerized rats also reversed hypertension. HSP70 gene delivery to the renal vein of the kidneys of rats sensitized to HSP70 caused an increment in blood pressure in response to a high-salt diet. The HSP70 peptide used in this work induces a strong proliferative response in peripheral blood lymphocytes of patients with essential hypertension. These studies provide evidence that autoimmunity plays a role in salt-sensitive hypertension and identifies HSP70 expressed in the kidney as one key antigen. These findings raise the possibility of novel approaches to the treatment of this condition.

Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg·kg⁻¹·day⁻¹ by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone ( n = 5) or neither lead nor MMF ( n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-κB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-κB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage. Background Chronic renal disease is associated with oxidative stress and reduced nitric oxide availability which, in turn, promotes hypertension and further progression of renal damage. Most actions of nitric oxide are mediated by cyclic 3′,5′ guanosine monophosphate (cGMP) which is rapidly degraded by phosphodiesterases (PDE). Therefore, we investigated if inhibition of PDE-5 would retard the progression of chronic renal failure. Methods We studied rats with 5/6 nephrectomy treated with sildenafil (2.5 mg/kg^-1/day^-1) in two experimental protocols. In the first protocol, we started sildenafil therapy immediately after renal ablation and continued treatment for 8 weeks. Control groups consisted of rats with renal ablation treated with drug-free vehicle and sham-operated rats with and without sildenafil treatment. Results In these studies, sildenafil treatment prevented hypertension and deterioration of renal function, reduced histologic damage, inflammation and apoptosis, delayed the onset of proteinuria, and preserved renal capillary integrity. In the second protocol we compared sildenafil with losartan (7.5 mg/kg^-1/day^-1) and the combination of both drugs in established renal disease, starting these drugs 4 weeks after 5/6 nephrectomy. Delayed sildenafil treatment failed to improve proteinuria and glomerulosclerosis but ameliorated hypertension and azotemia. Conclusion These observations suggest that currently available PDE-5 inhibitors have potential clinical value in the treatment of chronic renal disease.