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.

A large number of investigations have demonstrated the participation of the immune system in the pathogenesis of hypertension. Studies focusing on macrophages and Toll-like receptors have documented involvement of the innate immunity. The requirements of antigen presentation and co-stimulation, the critical importance of T cell-driven inflammation, and the demonstration, in specific conditions, of agonistic antibodies directed to angiotensin II type 1 receptors and adrenergic receptors support the role of acquired immunity. Experimental findings support the concept that the balance between T cell-induced inflammation and T cell suppressor responses is critical for the regulation of blood pressure levels. Expression of neoantigens in response to inflammation, as well as surfacing of intracellular immunogenic proteins, such as heat shock proteins, could be responsible for autoimmune reactivity in the kidney, arteries, and central nervous system. Persisting, low-grade inflammation in these target organs may lead to impaired pressure natriuresis, an increase in sympathetic activity, and vascular endothelial dysfunction that may be the cause of chronic elevation of blood pressure in essential hypertension.

The development of stress drives a host of biological responses that include the overproduction of a family of proteins named heat shock proteins (HSPs), because they were initially studied after heat exposure. HSPs are evolutionarily preserved proteins with a high degree of interspecies homology. HSPs are intracellular proteins that also have extracellular expression. The primary role of HSPs is to protect cell function by preventing irreversible protein damage and facilitating molecular traffic through intracellular pathways. However, in addition to their chaperone role, HSPs are immunodominant molecules that stimulate natural as well as disease-related immune reactivity. The latter may be a consequence of molecular mimicry, generating cross-reactivity between human HSPs and the HSPs of infectious agents. Autoimmune reactivity driven by HSPs could also be the result of enhancement of the immune response to peptides generated during cellular injury and of their role in the delivery of peptides to the major histocompatibility complex in antigen-presenting cells. In humans, HSPs have been found to participate in the pathogenesis of a large number of diseases. This review is focused on the role of HSPs in atherosclerosis and essential hypertension.

Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD.