Hypertension and The Kidneys

For their size, the kidneys do an awful lot of work. Besides filtering the blood of potentially harmful substances, they secrete hormones that influence the manufacture of red blood cells and the absorption and metabolism of calcium. Another job is to monitor blood pressure and to take corrective action if it drops. The kidney does this by secreting a proteolytic enzyme called renin (not to be confused with rennin, the bovine enzyme that curdles milk and is used to make cheeses and junkets), whose function is to control another hormone, angiotensin, the polypeptide that constricts blood vessels. Angiotensin, especially angiotensin 2, is occasionally the target of blood pressure medications. This compound constricts the walls of arterioles and closes capillary beds, causing the kidney to reabsorb sodium while stimulating the adrenal cortex to release aldosterone, itself encouraging the kidney to reclaim still more sodium and, therefore, water. To add to this complicated cycle, angiotensin 2 prompts the pituitary to secrete vasopressin, yet another hormone that constricts blood vessels and elevates blood pressure, but also reduces excretion of urine by causing the kidney to reabsorb water. Because of this activity, vasopressin is also known as antidiuretic hormone, which conserves water stores in times of dehydration. All this spirited activity is directed by the brain.

We all realize that blood pressure (BP) involves the heart. In response to elevated BP, the heart releases two natriuretic peptides, type A and type B. (natri from ‘sodium’ and uretic from urine). These hormones relax the arterioles, inhibit the secretion of renin and aldosterone, and constrain the reabsorption of sodium ions by the kidney. This reduces reabsorption of water, so the volume of urine increases along with the volume of sodium in it. The net effect is to lower BP by reducing the volume of blood in the circulatory system. Whew! If ever you have heard the expression from Psalm 139:14 that mentions man being fearfully and wonderfully made, you now know what it means.

High blood pressure, usually anything above 140/90, can be caused by a number of things, including overweight, race, age, diet and exercise, family history, smoking, alcohol and stress levels. Healthy lifestyle can help. If there is such a thing as a worldwide hypertension epidemic, it may now be addressed by tackling a newfound cellular source in the brain, the targeting of which can reverse the condition. It has been found that angiotensin 2 is causative of hypertension because of the dysregulation of certain brain mechanisms involving the endoplasmic reticulum (Young, 2012).

The Endo What? The endoplasmic reticulum is common to all eukaryotic cells—those that have a membrane-bound nucleus, genetic material organized within chromosomes, and organelles, such as mitochondria, chloroplasts…and endoplasmic reticula (ER). The ER is a network of membranes important to protein synthesis and folding, and it helps in the transport of cellular materials. The actual job of the ER varies from cell type to cell type, and occasionally within the same cell, depending on whether it is smooth or rough. The smooth ER is shaped like a tube and synthesizes phospholipids, which are the chief constituents of cell membranes. It also breaks down toxins in the liver, helps to regulate calcium concentrations, and controls the metabolism of carbohydrates. The rough ER is a line of flattened sacs with little bumps called ribosomes on the outside. This is where serum proteins, such as albumin, are synthesized.

Back To BP Researchers have recently found that a water-soluble (hydrophilic) bile acid called tauroursodeoxycholic acid (TUDCA) reduces stress to the endoplasmic reticulum, which acts as a stress manager for every cell. If something goes wrong in a cell, the ER starts processes that help adapt to the stressors, angiotensin 2 among them. Because different ER’s do different jobs, only those that orchestrate the cascade of events causing hypertension are influenced by TUDCA. These are located outside the blood-brain barrier, near the bottom, allowing them to be affected by substances that are too large to cross the barrier, such as certain medications. Nonetheless, these ER’s are able to communicate with the brain’s inner chambers. TUDCA may then be able to treat the stress on hypertension-related endoplasmic reticula that control the release of angiotensin 2 (Young, 2012).

Chronic metabolic disorders, such as obesity, diabetes and insulin resistance are also mediated by the ER’s failure or success in launching an adequate stress defense.  Insulin resistance associated with the production of inflammatory factors, both related to fat cells, can activate the ER stress pathway. Research at the Hallet Diabetes Center of Brown University discovered that TUDCA reduces inflammatory signaling and thus may attenuate the ER stressors that trigger blood pressure elevation (Jiao, 2011). Additional study of intracellular regulatory proteins found that regular treatment with TUDCA lowers systolic blood pressure while lessening glucose intolerance (Ceylan-Isik, 2011).

Overactivity of the renin-angiotensin system, for which the kidneys are partly responsible, leads to the vasoconstriction that characterizes hypertension. It is easier to control angiotensin than renin, so angiotensin-related drugs are used, such as ACE inhibitors or angiotensin-receptor blockers (ARBs). It is renin that converts angiotensin. Renin blockers demonstrate poor bioavailability, so are rarely used. To avoid the side effects that accompany drugs, sodium reduction is the first step of a natural protocol in giving the kidneys a break and reducing BP. Following the DASH diet (Dietary Approaches to Stop Hypertension) is not a difficult strategy (Sacks, 2001) (Svetkey, 1999). Water will clear wastes from the kidneys, acidulation being recommended. Increase vegetable intake while reducing meat, especially red. Fill half the plate or more with produce. To bless the kidneys and to control BP add omega-3 fatty acids to the daily regimen (Friedman, 2010) (Cabo 2012) (Mori, 2010). If urine is any darker than a manila folder, drink more water.

Amin A, Choi SK, Galan M, Kassan M, Partyka M, Kadowitz P, Henrion D, Trebak M, Belmadani S, Matrougui K. Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice. J Pathol. 2012 Jun;227(2):165-74.

Aneja A, El-Atat F, McFarlane SI, Sowers JR. Hypertension and obesity. Recent Prog Horm Res. 2004;59:169-205.

Cabo J, Alonso R, Mata P. Omega-3 fatty acids and blood pressure Br J Nutr. 2012 Jun;107 Suppl 2:S195-200.

Ceylan-Isik AF, Sreejayan N, Ren J. Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction. J Mol Cell Cardiol. 2011 Jan;50(1):107-16.

Colin N. Young, Xian Cao, Mallikarjuna R. Guruju, Joseph P. Pierce, Donald A. Morgan, Gang Wang, Costantino Iadecola, Allyn L. Mark, Robin L. Davisson ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension J Clin Inv. November 1, 2012; Volume 122, issue 11: 3960

Esler M, Jennings G, Biviano B, Lambert G, Hasking G. Mechanism of elevated plasma noradrenaline in the course of essential hypertension. J Cardiovasc Pharmacol. 1986;8 Suppl 5:S39-43.

Esler M. High blood pressure management: potential benefits of I1 agents. J Hypertens Suppl. 1998 Aug;16(3):S19-24.

Esler M, Kaye D. Sympathetic nervous system activation in essential hypertension, cardiac failure and psychosomatic heart disease. J Cardiovasc Pharmacol. 2000;35(7 Suppl 4):S1-7.

Friedman AN. Omega-3 fatty acid supplementation in advanced kidney disease. Semin Dial. 2010 Jul-Aug;23(4):396-400.

Hall JE, Brands MW, Henegar JR. Mechanisms of hypertension and kidney disease in obesity. Ann N Y Acad Sci. 1999 Nov 18;892:91-107.

Hall JE. The kidney, hypertension, and obesity. Hypertension. 2003 Mar;41(3 Pt 2):625-33.

Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010 Mar 19;140(6):900-17. doi: 10.1016/j.cell.2010.02.034.

Jiao P, Ma J, Feng B, Zhang H, Diehl JA, Chin YE, Yan W, Xu H. FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKβ pathways. Obesity (Silver Spring). 2011 Mar;19(3):483-91.

Koji Sakai, Khristofor Agassandian, Satoshi Morimoto, Puspha Sinnayah, Martin D. Cassell, Robin L. Davisson, and Curt D. Sigmund Local production of angiotensin II in the subfornical organ causes elevated drinking J Clin Invest. 2007 April 2; 117(4): 1088–1095.

Mori TA Omega-3 fatty acids and blood pressure. Cell Mol Biol (Noisy-le-grand). 2010 Feb 25;56(1):83-92.

Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG Jr, Ozcan U. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009 Jan 7;9(1):35-51.

Purkayastha S, Zhang H, Zhang G, Ahmed Z, Wang Y, Cai D. Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2939-44. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER 3rd, Simons-Morton DG, Karanja N, Lin PH; DASH-Sodium Collaborative Research Group.

Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001 Jan 4;344(1):3-10.

Schulman IH, Zhou MS, Raij L. Interaction between nitric oxide and angiotensin II in the endothelium: role in atherosclerosis and hypertension. J Hypertens Suppl. 2006 Mar;24(1):S45-50.

Svetkey LP, Simons-Morton D, Vollmer WM, Appel LJ, Conlin PR, Ryan DH, Ard J, Kennedy BM. Effects of dietary patterns on blood pressure: subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med. 1999 Feb 8;159(3):285-93.

Wilcox CS. Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regul Integr Comp Physiol. 2005 Oct;289(4):R913-35.