Mechanisms of Impaired Urinary Concentrating Ability in Adult Rats Treated Neonatally with Enalapril
| Title: | Mechanisms of Impaired Urinary Concentrating Ability in Adult Rats Treated Neonatally with Enalapril |
|---|---|
| Authors: | Nielsen, Soren; Guron, Gregor; Nilsson, Annika; Nitescu, Nicoleta; Sundelin, B.; Frokiaer, Jorgen; Friberg, MD, PhD, Peter |
| Publisher: | Acta Physiologica Scandinavica |
| Date Published: | January 01, 1999 |
| Reference Number: | 227 |
Neonatal angiotensin-converting enzyme inhibition or angiotensin II type-1 receptor blockade induces irreversible renal histological abnormalities and an impaired urinary concentrating ability in the rat. The aim of the present study was to determine the pathophysiological mechanisms underlying the defect in urine concentration in adult rats treated neonatally with enalapril. Male Wistar rats received daily intraperitoneal injections of enalapril (10 mg kg(-1)) or saline vehicle from 3 to 24 days of age. Assessments of fluid handling and maximal urine osmolality (Uosm(max)), renal function and tubular free water reabsorption (T(c)H2O) under pentobarbital anaesthesia, renal tissue solute concentrations, renal aquaporin-2 (AQP2) expression, and kidney histology, were performed in 12-16-week-old rats. Uosm(max) (1488 +/- 109 vs. 2858 +/- 116 mOsm kg(-1), P < 0.05) and maximal T(c)H2O were reduced in enalapril- vs. vehicle-treated rats after administration of 1-desamino-8-D-arginine vasopressin. Neonatally enalapril-treated rats showed marked papillary atrophy, a decrease in medullary tissue solute concentrations, and a reduction in AQP2 expression specifically in the inner medulla. Glomerular filtration rate, renal plasma flow and urinary excretion rates of sodium, potassium and chloride did not differ between groups. In conclusion, adult rats treated neonatally with enalapril showed a urinary concentrating defect of renal origin which primarily could be explained by the papillary atrophy. However, an impaired ability to generate medullary interstitial hypertonicity, and a decrease in inner medullary AQP2 expression, also seem to contribute to this defect.
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
The polyuria and polydipsia give evidence to the fact that the kidneys of RAS-damaged rats lose their ability to concentrate urine. Besides being vital for maintaining body water balance, and thus health, the urine concentrating process is complex. It involves the nephrons, which are the main working units of the kidney, each consisting of a filter called a glomerulus and a tiny tube called a tubule. The tubule, looking like a string of spaghetti, reaches from the outermost regions of the kidney (i.e. cortex) to the innermost regions (i.e. the inner medulla). The same goes for the collecting duct (CD) that the tubules connect with.
There are about a million nephrons in each kidney. Together with the kidney inner tissue (the interstitium) they create the proper osmotic conditions necessary for the water flowing through the tubules and CDs to be reabsorbed by the interstitium. It is the reabsorption of this body water that leaves behind concentrated urine and helps balance body water.
Enalapril is an angiotensin-converting enzyme inhibitor. Given to newly born rats over a three to four week period, it blocks the RAS. This leaves the rats unable to concentrate their urine. In this article, Guron, et al., report on their experiments devised to understand the mechanisms that cause the defect in urine concentration observed in rats treated with enalapril after birth.
The experimental group of rats were injected with enalapril daily from the age of 3 days to 24 days. When the rats reached their adult stage (12 - 16 weeks) they were assessed for how their kidneys handled body fluid, how effectively their kidneys could produce concentrated urine and reabsorb water from the kidney tubules. The authors also checked the rats for their ability to express aquaporin-2s (AQP2s) in the principal cells of the kidney CD. (AQP2s are an essential part of the urine concentrating process.) They also checked the rats' kidney tissue for signs of abnormality.
The main finding of the authors' study was that the reason the enalapril-treated rats could not concentrate their urine was because their kidneys were unable to reabsorb the body water flowing through the section of the CDs located in the medulla of the kidney (i.e. the medullary CDs). The kidney could not do so because the inner portions of the kidney (the papillary portions of the kidney, including the inner medullary collecting ducts (IMCDs)) were atrophied.
The atrophy in the region reduces the area where urea and body water are reabsorbed. Compounding this was the rat kidneys' inability to generate the proper osmotic conditions for water and urea exchange between the tubules and the kidney interstitium. Generating the proper osmotic conditions requires the full length of the tubule. Having the tips of the tubules, as well as the IMCDs, atrophied takes away the needed length to generate the proper conditions. Thus, the proper amount of water could not be reabsorbed so the urine could not be concentrated. All the water that could not be reabsorbed was shunted to the bladder as dilute urine.
The authors also found that enalapril-treated rats showed a marked decrease in the number of AQP2s expressed in the inner medulla. This would further reduce the kidneys' ability to concentrate urine. Since their expression of AQP2 was not reduced in the outer medulla and cortex, the down-regulation of AQP2 in the inner medulla was unlikely to be caused by changes in circulating levels of AVP.
This study demonstrates an important role for the RAS in developing and maintain the normal shape and function of the rat kidney inner medulla.