Pathogenesis of essential hypertension: historical paradigms and modern insights

Abstract

Since its first identification in the late 1800s, a variety of etiologies for essential hypertension have been proposed. In this paper we review the primary proposed hypotheses in the context of both the time in which they were proposed as well as the subsequent studies performed over the years. From these various insights, we propose a current paradigm to explain the renal mechanisms underlying the hypertension epidemic today. Specifically, we propose that hypertension is initiated by agents that cause systemic and intrarenal vasoconstriction. Over time intrarenal injury develops with microvascular disease, interstitial T cell and macrophage recruitment with the induction of an autoimmune response, with local angiotensin II formation and oxidant generation. These changes maintain intrarenal vasoconstriction and hypoxia with a change in local vasoconstrictor-vasodilator balance favoring sodium retention. Both genetic and congenital (nephron number) mechanisms have profound influence on this pathway. As blood pressure rises, renal ischemia is ameliorated and sodium balance restored completely (in salt-resistant) or partially (in salt-sensitive) hypertension, but at the expense of a rightward shift in the pressure natriuresis curve and persistent hypertension.

Hypoxia: The Force that Drives Chronic Kidney Disease

“…[141][142][143] Constriction of blood vessels limits blood flow and consequently reduces oxygen delivery to the kidney. [14][15][16][17] In addition, hypertension leads the kidney to consume approximately twice as much oxygen as normal to transport a given amount of sodium.…”

Uric acid and hypertension: an age-related relationship?

“…5 This may relate to the development of age-related renal microvascular disease, glomerulosclerosis and capillary rarefaction. 6 Experimental studies suggest that renal microvascular disease is a major mechanism for inducing saltsensitive hypertension even in the absence of reduced GFR 7 and this could contribute to the marked increase in salt-sensitivity that is observed in aging individuals. 8 Other factors are also likely involved, such as the increasing prevalence of obesity and metabolic syndrome that occurs with age.…”

Does immunosuppressant medication lower blood pressure and arterial stiffness in patients with chronic kidney disease? An observational study

“…There are now several reports that immunosuppression lowers blood pressure in non-immunological experimental models of hypertension and renal disease. 37 There is also an intriguing preliminary report of mycophenolate mofetil lowering blood pressure in eight patients with rheumatoid arthritis or psoriasis. 38 However, to the best of our knowledge, this is the first report in which long-term immunosuppression appears to be associated with reduced use of antihypertensive medication in a human population.…”