Ethan Zinsmeister

Introduction. Hypertension is a prominent disease in the United States and the world with over 45% of adults in the United States being hypertensive and hypertension being the leading cause of death and disability in the world.^1,2 Salt-sensitive hypertension is a type of hypertension defined as “changes in blood pressure that parallels changes in salt intake”.² The immune system, specifically proinflammatory cytokines such as TNF-alpha, interferon-gamma, and interleukin-1B, have been found to contribute to the development of hypertension, but the mechanism is unclear.^1,3 The WNK-SPAK-NCC pathway is responsible for reabsorption of sodium in the kidney and is regulated by the ligase NEDD4-2 which degrades WNK1.⁴ Methods. The effects of TNF-alpha on this pathway were studied using mouse models of chronic kidney disease that were fed normal or high salt diets.⁴ The kidneys of these mice were then stained to determine if there were proinflammatory cytokines present.⁴ Results. The mice fed high salt diets had statistically higher systolic blood pressures than those fed normal diets, and TNF-alpha was found to be increased in the high salt diet fed mice. TNF-alpha increased the amount of WNK1 present to phosphorylate SPAK and NCC so more sodium was reabsorbed leading to salt-sensitive hypertension.⁴ It was found that TNF-alpha increases the amount of WNK1 by inhibiting the expression of NEDD4-2 so more WNK1 is present.⁴ The TNF-alpha inhibitor etanercept was administered to the mice and it was found to reverse the actions that TNF-alpha had on the mice: the systolic blood pressure decreased significantly, the amount of phosphorylated WNK, SPAK, and NCC all decreased, and the amount of NEDD4-2 present increased.⁴ Conclusion. TNF-alpha can be used as a target for salt-sensitive hypertension, however more research needs to be done to limit the inhibition to the kidneys due to the important role TNF-alpha plays in the immune response to infection.⁴ TNF-alpha can also be used as an indicator for prescribing thiazide diuretics to treat salt-sensitive hypertension as patients with TNF-alpha induced hypertension have been found to respond well to these drugs.⁴ Further study of this mechanism, and other mechanisms that lead to the development of salt-sensitive hypertension, needs to be done so more targeted therapeutics can be developed. Currently the medications available for salt-sensitive hypertension work to control the symptoms, but if we knew more about the root cause, then we could target it better.⁵

1.  Mattson DL, Dasinger JH, Abais-Battad JM. Amplification of Salt-Sensitive Hypertension and Kidney Damage by Immune Mechanisms. Am J Hypertens. 2021;34(1):3-14. doi:10.1093/ajh/hpaa124
2. Elijovich F, Kleyman TR, Laffer CL, Kirabo A. Immune Mechanisms of Dietary Salt-Induced Hypertension and Kidney Disease: Harry Goldblatt Award for Early Career Investigators 2020. Hypertension. 2021;78(2):252-260. doi:10.1161/HYPERTENSIONAHA.121.16495
3. Rucker AJ, Rudemiller NP, Crowley SD. Salt, Hypertension, and Immunity. Annu Rev Physiol. 2018;80:283-307. doi:10.1146/annurev-physiol-021317-121134
4. Furusho T, Sohara E, Mandai S, et al. Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease. Kidney Int. 2020;97(4):713-727. doi:10.1016/j.kint.2019.11.021
5. Lu X, Crowley SD. Inflammation in Salt-Sensitive Hypertension and Renal Damage. Curr Hypertens Rep. 2018;20(12):103. Published 2018 Oct 30. doi:10.1007/s11906-018-0903-x