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Subtitle: The Balance of Nitric Oxide, Peroxinitrite, and NO donors in Maintenance of Renal Function

Curator and Author: Larry H. Bernstein, MD, FCAP

The Nitric Oxide and Renal is presented in FOUR parts:

Part I: The Amazing Structure and Adaptive Functioning of the Kidneys: Nitric Oxide

Part II: Nitric Oxide and iNOS have Key Roles in Kidney Diseases

Part III: The Molecular Biology of Renal Disorders: Nitric Oxide

Part IV: New Insights on Nitric Oxide donors 

Conclusion to this series is presented in

The Essential Role of Nitric Oxide and Therapeutic NO Donor Targets in Renal Pharmacotherapy

Evolution of kidney function

The Emergence of  a Mammalian Kidney as Subterranian Life Crawls from Sea to Land
In fish the nerves that activate breathing take a short journey from an ancient part of the brain, the brain stem, to the throat and gills. For the ancient tadpole, the nerve controlling a reflex related to hiccup in man served a useful purpose, allowing the entrance to the lung to remain open when breathing air but closing it off when gulping water – which would then be directed only to the gills. For humans and other mammals it provides a bit of evidence of our common ancestry. DNA evidence has pinned iguanas and chameleons as the closest relatives to snakes.

In utero, we develop three separate kidneys in succession, absorbing the first two before we wind up with the embryonic kidney that will become our adult kidney. The first two of these reprise embryonic kidneys of ancestral forms, and in the proper evolutionary order. The pronephric kidney does not function in human and other mammalian embryos. It disappears and gives rise to the Mesonephric kidney. This kidney filters wastes from the blood and excretes them to the outside of the body via a pair of tubes called the mesonephric ducts (also “Wolffian ducts”). The mesonephric kidney goes on to develop into the adult kidney of fish and amphibians. This kidney does function for a few weeks in the human embryo, but then disappears as our final kidney forms, which is the Metanephric kidney.

The Metanephric kidney begins developing about five weeks into gestation, and consists of an organ that filters wastes from the blood and excretes them to the outside through a pair ureters. In the embryo, the wastes are excreted directly into the amniotic fluid. The metanephric kidney is the final adult kidney of reptiles, birds, and mammals. The first two kidneys resemble, in order, those of primitive aquatic vertebrates (lampreys and hagfish) and aquatic or semiaquatic vertebrates (fish and amphibians): an evolutionary order. The explanation, then, is that we go through developmental stages that show organs resembling those of our ancestors.

Take a step back and we see that fresh water fish have glomerular filtration. Cardiac contraction provides the pressure to force the water, small molecules, and ions into the glomerulus as nephric filtrate. The essential ingredients are then reclaimed by the tubules, returning to the blood in the capillaries surrounding the tubules. The amphibian kidney also functions chiefly as a device for excreting excess water. But the problem is to conserve water, not eliminate it. The frog adjusts to the varying water content of its surroundings by adjusting the rate of filtration at the glomerulus. When blood flow through the glomerulus is restricted, a renal portal system is present to carry away materials reabsorbed through the tubules. Bird kidneys function like those of reptiles (from which they are descended). Uric acid is also their chief nitrogenous waste.

All mammals share our use of urea as their chief nitrogenous waste. Urea requires much more water to be excreted than does uric acid. Thus, mammals produce large amounts of nephric filtrate but are able to reabsorb most of this in the tubules. Even so, humans lose several hundred ml each day in flushing urea out of the body. In his hypothesis of the evolution of renal function Homer Smith proposed that the formation of glomerular nephron and body armor had been adequate for the appearance of primitive vertebrates in fresh water and that the adaptation of homoisotherms to terrestrial life was accompanied by the appearance of the loop of Henle.

In the current paper, the increase in the arterial blood supply and glomerular filtration rate and the sharp elevation of the proximal reabsorption are viewed as important mechanisms in the evolution of the kidney. The presence of glomeruli in myxines and of nephron loops in lampreys suggests that fresh water animals used the preformed glomerular apparatus of early vertebrates, while mechanisms of urinary concentration was associated with the subdivision of the kidney into the renal cortex and medulla. The principles of evolution of renal functions can be observed at several levels of organizations in the kidney.
Natochin YV. Evolutionary aspects of renal function. Kidney International 1996; 49: 1539–1542; doi:10.1038/ki.1996.220.
Smith HW: From Fish to Philosopher. Boston, Little, Brown, 1953.

The Kidney: Anatomy and Physiology

The kidney lies in the lower abdomen capped by the adrenal glands. It has an outer cortex and an inner medulla. The basic unit is the nephron, which filters blood at the glomerulus, and not only filters urine eliminating mainly urea, also uric acid, and other nitrogenous waste, but also reabsorbs Na+ in exchange for H+/(reciprocal K+) through the carbonic anhydrase of the epithelium. In addition, it serves as a endocrine organ and receptor through the renin-angiotensin/aldosterone system, sensitivity to water loss controlled by distal acting antidiuretic hormone, and is sensitive to the natriuretic peptides of the heart. The kidney is an elegant structure with a high concentration of glomeruli in the cortex, and in the medulla one finds a U-shaped tube that is critical in functioning of a countercurrent multiplier system with a descending limb, Loop of Henley, and ascending limb.

The glomerulus is a dense ball of capillaries (glomerular capillaries) that branches from the afferent arteriole that enters the nephron. Because blood in the glomerular capillaries is under high pressure, substances in the blood that are small enough to pass through the pores (fenestrae, or endothelial fenestrations) in the capillary walls are forced out and into the encircling glomerular capsule. The glomerular capsule is a cup-shaped body that encircles the glomerular capillaries and collects the material (filtrate) that is forced out of the glomerular capillaries. The filtrate collects in the interior of the glomerular capsule, the capsular space, which is an area bounded by an inner visceral layer (that faces the glomerular capillaries) and an outer parietal layer.

The glomerular filtrate passes into the proximal convoluted tubule (PCT),  a winding tube in the renal cortex.  The PCT is mitochondria roch and has a high-energy yield.  The large surface area of these cells support their functions of reabsorption and secretion. The filtrate passes down the descending tubule and reaches the Loop of Henle. The  loop is shaped like a hairpin and consists of a descending limb that drops into the renal medulla and an ascending limb that rises back into the renal cortex.  The distal convoluted tubule (DCT) coils within the renal cortex and empties into the collecting duct.   In the final portions of the DCT and the collecting duct, there are cells that respond to the hormones aldosterone and antidiuretic hormone (ADH), and there are cells that secrete H⁺ in an effort to maintain proper pH.

The juxtaglomerular apparatus (JGA) is an area of the nephron where the afferent arteriole and the initial portion of the distal convoluted tubule are in close contact. Here, specialized smooth muscle cells of the afferent arteriole, called granular juxtaglomerular (JG) cells, act as mechanoreceptors that monitor blood pressure in the afferent arteriole. In the adjacent distal convoluted tubule, specialized cells, called macula densa, act as chemoreceptors that monitor the concentration of Na⁺ and Cl^– in the urine inside the tubule. Together, these cells help regulate blood pressure and the production of urine in the nephron.

The operation of the human nephron consists of three processes:

• Glomerular filtration
• Tubular reabsorption
• Tubular secretion

The net filtration pressure (NFP) determines the quantity of filtrate that is forced into the glomerular capsule. The NFP, estimated at about 10 mm Hg, is the sum of pressures that promote filtration less the sum of those that oppose filtration. The following contribute to the NFP:

• The glomerular hydrostatic pressure (blood pressure in the glomerulus) promotes filtration.
• The glomerular osmotic pressure  is created as a result of the movement of water and solutes out of the glomerular capillaries. The increase in the concentration of solutes in the glomerular capillaries draws into the glomerular capillaries.
• The capsular hydrostatic pressure inhibits filtration. This pressure develops as water collects in the glomerular capsule.

As the filtrate flows through the glomerulus into the descending limb, glucose is reabsorbed  to a threshhold maximum, and H+ is converted by the carbonic anhydrase  to water and CO2, except with serious acidemia, in which K+ is reabsorbed with H+ loss to the filtrate, resulting in a hyperkalemia. In the descending limb Na+ is absorbed into the interstitium, and the hypertonic interstitium draws water back for circulation, regulated by the action of ADH on the epithelium of the ascending limb. The result in terms of basic urinary clearance, the volume of urine loss is moderated by the amount needed for circulation (10 units of whole blood) without dehydration, and an amount sufficient for metabolite loss (including drug metabolites). The urine flows into the kidney pelvis and flow down the ureters.

The reabsorption of most substances from the tubule to the interstitial fluids requires a membrane-bound transport protein that carries these substances across the tubule cell membrane by active transport. When all of the available transport proteins are being used, the rate of reabsorption reaches a transport maximum (Tm), and substances that cannot be transported are lost in the urine.

The blood reaches the glomerulus by way of the afferent arteriole and leaves by way of the efferent arteriole. In a book by the Harvard Pathologist Shields Warren on diabetes he made a distinction between hypertension and diabetes in that efferent arteriolar sclerosis is present in both, but diabetes is uniquely identified by afferent arteriolar sclerosis. In diabetes you also have a typical glomerulosclerosis, which might be related to the same hyalinization found in the pancreatic islets – a secondary amyloidosis.

The renal artery for each kidney enters the renal hilus and successively branches into segmental arteries and then into interlobar arteries, which pass between the renal pyramids toward the renal cortex. The interlobar arteries then branch into the arcuate arteries, which curve as they pass along the junction of the renal medulla and cortex. Branches of the arcuate arteries, called interlobular arteries, penetrate the renal cortex, where they again branch into afferent arterioles, which enter the filtering mechanisms, or glomeruli, of the nephrons.

Summary

The criticality of renal function is traced to the emergence of animal forms from the sea to land, and its evolutionary change is recapitulated in the embryo.  We have already described the key role that nitric oxide and the NO synthases play in reduction of oxidative stress, and we have seen that a balance has to be struck between pro- and anti-oxidative as well as inflammatory elements for avoidance of diseases, specifically involving the circulation, but effectively not limited to any organ system. In addition, we have noted the importance of oxidative stress and modifications in mitochondrial function in oncogenesis related to a reliance on aerobic glycolysis to support both energy and synthetic activities in growth and proliferation of the “cancer” cell, that becomes more like a cancer “prototype” than its forebears.  In this discussion we pay attention to kidney function, and what follows is the adaptive role of NO and NO donors. This is an extension of a series of posts on NO and NO related disorders.

Frontal section through the kidney (Photo credit: Wikipedia)

Structures of the kidney: Renal pyramid Interlobar artery Renal artery Renal vein Renal hylum Renal pelvis Ureter Minor calyx Renal capsule Inferior extremity Superior extremity Interlobar vein Nephron Renal sinus Major calyx Renal papilla Renal column (no distinction for red/blue (oxygenated or not) blood, arteriole is between capilaries and larger vessels) (Photo credit: Wikipedia)

Distribution of blood vessels in cortex of kidney. (Although the figure labels the efferent vessel as a vein, it is actually an arteriole.) (Photo credit: Wikipedia)

English: Nephron, Diagram of the urine formation. The number inside tubular urine concentration in mOsm/l – when ADH acts  (Photo credit: Wikipedia)

Anatomy of the Kidneys. CliffsNotes. www.cliffsnotes.com/…/Anatomy-of-the-Kidneys