Macula Densa

Control of the Circulating RAAS

June 23, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , ,

The activity of the circulating RAAS is governed by the amount of renin secreted by the granular cells of the jg (juxtaglomerular) apparatus. There are 3 major controllers of renin secretion.

PS: Look at the RAAS, plasma angiotensinogen is synthesized in the liver and plasma angiotensinogen levels are normally high therefore do not limit the production of AII. Furthermore, ACE is expressed on the endothelial surfaces of the vascular system, particularly the pulmonary vessels, and avidly converts most of the angiotensin I into AII. Therefore, the major determinant of circulating AII is the amount of renin available to form angiotensin I.

The first contoller is sympathetic input. Norepinephrine released from postganglionic sympathetic neurons acts on beta1-adrenergic receptors in the granular cells. This activates a c-AMP-mediated pathway that causes the release of renin. The granular cells are quite sensitive to norepinephrine and respond to low levels of sympathetic activity that may have minimal direct effect on the renal vasculature or sodium transport.

The second controller of renin secretion is pressure in the afferent arteriole. The granular cells not only respond to vascular pressures indirectly via adrenergic stimulation, they respond directly to changes in afferent arteriolar pressure. When pressure in the afferent arteriole decreases, renin production increases. Except in cases of major renal arterial blockage, pressure in the arteriolar lumen at the granular cells is close to systemic arterial pressure and changes in parallell with it. Because the granular cells respond to vascular pressure, they are acting as baroreceptors. In fact, the granular cells are the intrarenal baroreceptors. Even though they are not neurons and do not send afferent feedback, they are baroreceptors nevertheless. Consider what happens when arterial pressure drops. The intrarenal baroreceptors (the granular cells) sense the drop in pressure and increase their secretion of renin. Simultaneously, the drop in pressure is also sensed by the arterial baroreceptors in the carotid arteries and aorta. The fall in their afferent signaling allows the vasomotor center to increase sympathetic drive to the granular cells, resulting in a huge combined stimulation of renin secretion.

The third contoller of renin release originates from another component of the jg apparatus; namely the macula densa. The operation of the macula densa is somewhat complicated, but serves as a fascinating example of negative feedback in biological systems. The meacula densa is a detection system and initiator of feedback that helps regulate renin secretion and GFR (tubuloglomerular feedback/TG feedback). For the regulation of GFR please refer to thread "Factors That Affect GFR" at http://www.tomhsiung.com/wordpress/2014/04/factors-that-affect-gfr/. The macula densa is located at the end of the loop of Henle where the tubule passes between the afferent and efferent arterioles of Bowman's capsulre. It is able to sense flow and salt content in the tubular lumen that are the net result of filtration and reabsorption in tubular elements preceding it, that is, it sense "everything done so far." Flow is sensed by cilia that project into the tubular lumen from macula densa cells. Bending of the cilia initiates intracellular signaling that leads to release of paracrine mediators. Tubular sodium chloride is sensed by uptake via Na-K-2Cl multiporters whose action changes ionic concentrations within the macula densa cells and also causes release of paracrine mediators.

When tubular flow and sodium content are high it is as if "the body has too much sodium" and "GFR is too high." The mediators released by the macula densa reduce the secretion of renin (thereby allowing more sodium excretion) and decrease GFR (restoring GFR to an appropriate level). The immediate mediators is ATP, which is converted extracellularly to adenosine. One or both bind to purinergic receptors on the nearby granular cells. This has the effect of increasing intracellular calcium and reducing the release of renin. In turn, the reduction in renin secretion reduces the levels of AII and allows the kidneys to excrete more of the filtered sodium. Simultaneously, the adenosine binds to purinergic receptors on afferent arteriole smooth muscle. The subsequent rise in calcium in these cells stimulates contraction, thus reducing pressure and flow through the glomerular capillaries and reducing GFR.

What happens in the opposite case? Now "the body has too little sodium" and "GFR is too low." This initiates the release of different mediators, specifically prostaglandins and nitric oxide. In the granular cells the prostaglandins stimulate or prolong the lifetime of c-AMP, thereby stimulating the release of renin. In the afferent arterioles NO is a dilator of smooth muscle. The effect is to raise flow and pressure in the glomerular capillaries, and restore GFR to an appropirate level.

Histology of Renal Tubules and Capillaries

October 8, 2015 Nephrology, Physiology and Pathophysiology No comments , , , , , ,

Renal Tubule

The renal tubule begins at and leads out of Bowman’s capsule on the side opposite the vascular pole (the tubule pole, compare the Arctic pole and Antarctic pole of Earth). The tubule has a number of segments divided into subdivisions. Throughout its length the tubule is made up of a single layer of epithelial cells resting on basement membrane and connected by tight junctions that physically link the cells together.

Renal tubule segments include proximal convoluted tubule, proximal straight tubule, descending thin limb of the loop of Henle, the ascending thin limb of the loop of Henle (only long loop nephrons), ascending thick limb of the loop of Henle, distal convoluted tubule, connecting tubule, and collecting duct.

The proximal tubule is the first segment. It drains Bowman’s capsule and consists of a coiled segment – the proximal convoluted tubule – followed by a shorter straight segment – the proximal straight tubule. The coiled segment is entirely within the cortex, whereas the straight segment descends a short way into the outer medulla. Most of the length and functions of the proximal tubule are in the cortex. The next segment is the descending thin limb of the loop of Henle. The descending thin limbs of all nephrons begin at the same level, at the point where they connect to straight portions of proximal tubules in the outer medullaThis marks the border between the outer and inner stripes of the outer medulla.

In contrast, the descending thin limbs of different nephrons penetrate down to varying depths in the medulla. At their ending they abruptly reverse at a hairpin turn and become an ascending portion of the loop of Henle parallel to the descending portion. In long loops, the ones that have penetrated deep into the inner medulla, the epithelium of the first portion of the ascending limb remains thin, although different functionally from that of the descending limb. This segment is called the ascending thin limb of Henle’s loop, or simple the ascending thin limb. Further up the ascending portion the epithelium thickens, and this next segment is called the thick ascending limb. In short loops, there is no ascending think portion, and the thick ascending portion begins right at the hairpin loop.

All thick ascending limbs begin at the same level, which marks the border between the inner and outer medulla. Therefore, the thick ascending limbs begin at a slight deeper level in the medulla than do thin descending limbs. Each thick ascending limb rises back into the cortex right back to the very same Bowman’s capsule from which the tubule originated. Here it passes directly between the afferent and efferent arterioles at the vascular pole of Bowman’s capsule. The cell in the thick ascending limb closest to Bowman’s capsule (between the afferent and efferent arterioles) are specialized cells known as the macula densa. The macula densa marks the end of the thick ascending limb and the beginning of the distal convoluted tubule. This is followed by the connecting tubule, which leads to the cortical collecting duct, the first portion of which is called the initial collecting tubule. Connecting tubules from several nephrons merge to form a given cortical collecting duct.

All the cortical collecting ducts then run downward to enter the medulla and become outer medullary collecting ducts, and continue to become inner medullary collecting ducts. These merge to form larger ducts, the last portions of which are called papillary collecting ducts, each of which empties into a calyx of the renal pelvis. Each renal calyx is continuous with the ureter. The tubular fluid, now properly called urine, is not altered after it enters a calyx. Up to the distal convoluted tubule, the epithelial cells forming the wall of a nephrons in any given segment are homogeneous and distinct for that segment. For example, the thick ascending limb contains only thick ascending limb cells. However, beginning in the second half of the distal convoluted tubule the epithelium contains 2 intermingled cell types. The first constitutes the majority of cells in a particular segment and are usually called principal cells. Thus, there a segment-specific principal cells in the distal convoluted tubule, connecting tubule, and collecting ducts. Interspersed among the segment-specific cells in these regions are cells of a second type, called intercalated cells, that is, they are intercalated between the principal cells. The last portion of the medullary collecting duct contains neither principal cells nor intercalated cells but is composed entirely of a distinct cell type called the inner medullary collecting-duct cells.

Renal VesselsScreen Shot 2015-10-04 at 4.06.11 PM

Blood enters each kidney at the hilum via a renal artery. After several divisions into smaller arteries blood reaches arcuate arteries that course across the tops of the pyramids between the medulla and cortex. From these, cortical radial arteries project upward toward the kidney surface and give off a series of afferent arterioles (AAs), each of which leads to a glomerulus within Bowman’s capsule. These arteries and glomeruli are found only in the cortex, never in the medulla. In most organs, capillaries recombine to form the beginnings of the venous system, but the glomerular capillaries instead recombine to form another set of arterioles, the efferent arterioles (EAs). The vast majority of the EAs soon subdivide into a second set of capillaries called peritubular capillaries. These capillaries are profusely distributed throughout the cortex intermingled with the tubular segments. The peritubular capillaries then rejoin to form the veins by which blood ultimately leaves the kidney. EAs of glomeruli situated just above the corticomedullary border (juxtamedullary glomeruli) do not brach into peritubular capillaries the way most EAs do. Instead these arterioles descend downward into the outer medullar. Once in the medulla they divide many times to form buddies of parallel vessels called vasa recta. These bundles of vasa recta penetrate deep into the medulla.

Vasa recta on the outside of the vascular bundles “peel off” and give rise to interbundle networks of capillaries that surround Henle’s loops and the collecting ducts in the outer medullaOnly the center-most vasa recta supply capillaries in the inner medulla; thus, little blood flows into the papilla. The capillaries from the inner medulla re-form into ascending vasa recta that run in close association with the descending vasa recta within the vascular bundles. The structural and functional properties of the vasa recta are rather complex.