Summation of Basic Endocrine Data
George H. Gass, Harold M. Kaplan in Handbook of Endocrinology, 2020
Most renal nephrons lie close to the surface of the kidney and are called cortical nephrons. Those nephrons extending from the glomeruli that lie deep in the cortex are called juxtamed-ullary; these extend far down into the medulla of the kidney and then return to the cortex. Their epithelial cells in the distal tubule are called the macula densa; these send secretions toward the arterioles. Thus arterioles in close contact with the epithelial cells are packed with renin and are called juxtaglomerular cells. These cells plus the macula densa are called the juxtaglomerular complex. A paucity of sodium and chloride ions at the macula densa stimulates the juxtaglomerular cells to release active renin. This catalyzes angiotensin to increase the glomerular filtration rate. The ion concentrations may then return to normal levels and thus provide a feedback mechanism for constancy in renal function.
Renal physiology
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2015
In the juxtaglomerular apparatus, the macula densa lies in the wall of the ascending limb of the loop of Henle, close to the renal arterioles. The contraction of the smooth muscle of the afferent arteriole to the glomerulus is controlled by a vasoconstrictor, adenosine, from the macula densa (although the vasoconstrictor was previously thought to be renin). The macula densa releases more adenosine if the renal perfusion pressure rises and reduces production if the pressure falls. Adenosine production by the macula densa is determined by the composition of the fluid in the ascending loop of Henle. If the perfusion pressure increases, the glomerular capillary pressure and glomerular filtration also increase. The macula densa senses the increased flow of sodium and chloride in the ascending limb of the loop of Henle and releases more adenosine, which constricts the afferent arterioles, reducing the glomerular capillary pressure and the GFR. The vasodilator nitric oxide may be produced by the macula densa when the renal perfusion pressure falls.
Resuscitation Physiology
Kenneth D Boffard in Manual of Definitive Surgical Trauma Care: Incorporating Definitive Anaesthetic Trauma Care, 2019
Aldosterone secretion is increased by several mechanisms. The renin-angiotensin mechanism is the most important. When the glomerular arteriolar inflow pressure falls, the juxtaglomerular apparatus of the kidney secretes renin, which acts with angiotensinogen to form angiotensin I. This is converted to angiotensin II, a substance that stimulates production of aldosterone by the adrenal cortex. Reduction in sodium concentration stimulates the macula densa, a specialized area in the tubular epithelium adjacent to the juxtaglomerular apparatus, to activate renin release. An increase in plasma potassium concentration also stimulates aldosterone release. Volume losses and a fall in arterial pressure stimulate release of ACTH via receptors in the right atrium and the carotid artery.
Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors: epidemiology, pathophysiology, and treatment
Published in Expert Opinion on Drug Safety, 2020
Erasmia Sampani, Pantelis Sarafidis, Aikaterini Papagianni
The mechanisms that enable the SGLT-2 inhibitor to offer nephroprotection are under investigation. Following an elegant human study in young hyperfiltrating patients with T1DM that showed empagliflozin to reduce GFR together with effective renal plasma flow and to increase renal vascular resistance [28], it was suggested that SGLT-2 inhibitors could modulate the afferent arteriole tone through interference with the tubuloglomerular feedback mechanism [23]. In particular, the inhibition of renal glucose and sodium reabsorption in the proximal renal tubules is expected to increase the distal availability of sodium-chloride. The macula densa functions by sensing the increased sodium-chloride availability and through this restores the tubuloglomerular feedback resulting in a reversal of the vasodilation of the afferent arteriole; this decreases glomerular hyperfiltration, intraglomerular pressure, and albumin excretion [23,28]. However, a recent randomized trial examining the effects of dapagliflozin on renal microcirculation in 44 patients with T2DM, did not confirm the above findings [29]. In particular, dapagliflozin also reduced GFR but did not increase renal vascular resistance, suggesting that the reduction in intraglomerular pressure with SGLT-2 inhibitors is not due to vasoconstriction of the afferent but to vasodilation of the efferent arteriole. Thus, the mechanistic details of the SGLT-2 inhibitor action on kidney vasculature possibly need to be further investigated by larger studies.
The anti-hypertensive effects of sodium-glucose cotransporter-2 inhibitors
Published in Expert Review of Cardiovascular Therapy, 2023
Luxcia Kugathasan, Lisa Dubrofsky, Andrew Advani, David Z.I. Cherney
In contrast with a potential role for natriuresis, it is unlikely that the RAAS pathway contributes to the short-term antihypertensive effects of SGLT2 inhibitors, but it may help explain how BP reduction is maintained in certain patient groups. Although increased salt delivery to the macula densa should inhibit renin secretion, which would subsequently reduce BP, clinical studies demonstrate an increase in plasma renin activity and serum aldosterone following 12 weeks of dapagliflozin in patients with T2D [72]. The acute rise in systemic RAAS markers may be a compensatory mechanism in response to the transient diuretic action and subsequent volume depletion by SGLT2 inhibition [76,77]. However, this increase in renin activity and aldosterone concentration is reportedly lost after chronic intervention in patients with T2D, specifically after 6 months of SGLT2 inhibitor use [78]. It is postulated that other factors, including potassium and adrenocorticotropic hormone, may play a role in regulating aldosterone production, other than angiotensin II thereby limiting its rise long term [76]. This may perhaps implicate the RAAS in the prolonged reduction in BP with SGLT2 inhibitors but still does not explain how acute decreases in BP occur.
Dapagliflozin for the treatment of type 2 diabetes mellitus – an update
Published in Expert Opinion on Pharmacotherapy, 2021
Martha K Nicholson, Randa Ghazal Asswad, John PH Wilding
The benefits of dapagliflozin have also been shown to extend beyond glycemic control in the treatment of people with diabetes. These include lowering blood pressure, renal protection, and improved cardiac function [23], with mechanisms posited for this improvement including improved cardiac energy metabolism and prevention of adverse cardiac remodeling [24]. In T2DM, SGLT2 function is upregulated with increased reabsorption of glucose and sodium. Subsequently, decreased delivery of sodium distal to the PCT and macula densa eventually results in loss of tubuloglomerular feedback. This key autoregulatory mechanism adjusts the renal blood flow and glomerular filtration rate (GFR) to optimize fluid flow through the renal tubule. It is thought that SGLT2 inhibitors such as dapagliflozin enhance delivery of sodium to the macula densa to restore the tubuloglomerular feedback process, thus reducing intraglomerular pressure, reducing proteinuria, and helping to preserve renal function. Additionally, these renal mechanisms will inevitably have a positive impact on cardiovascular function as a secondary effect.
Related Knowledge Centers
- Autoregulation
- Blood Pressure
- Glomerulus
- Juxtaglomerular Cell
- Renin
- Cell Nucleus
- Blood Volume
- Kidney
- Cell
- Renin–Angiotensin System