Role of Transport in Chemically-Induced Nephrotoxicity *
Robin S. Goldstein in Mechanisms of Injury in Renal Disease and Toxicity, 2020
A third and perhaps equally important physiological mechanism that can underlie the development of nephrotoxicity is the ability of proximal tubular cells to transport a large variety of compounds from the blood into the cells. This process, coupled with the high renal blood flow, may explain how many nephrotoxicants have their primary effect on the proximal tubule. Most of the blood flow to the kidney is diverted to the cortex, where virtually all proximal tubular segments are located. In addition, these proximal tubular cells have the ability to transport various organic substances. Some variability exists as to which segment of the proximal tubule (SI, S2, S3) may show the greatest response to a given nephrotoxicant, and similarly, variability exists with respect to which segment has the greater ability to transport organic compounds. In the rabbit, the S2 segment appears to show the greatest activity, while in the rat the S3 segment is more active (Grantham, 1982; McKinney, 1982). Whatever the differences due to species or compound (transport substrate) variation, it is clear that the proximal tubule is the segment of the nephron most commonly affected by nephrotoxicants which cause acute tubular necrosis, and it is the proximal tubule where the secretory transport occurs. Few would doubt that the nephron site selectivity of some nephrotoxicants relates to the directional transport, or polarity, of proximal tubular cells.
Sodium Intake and Hypertension
Austin E. Doyle, Frederick A. O. Mendelsohn, Trefor O. Morgan in Pharmacological and Therapeutic Aspects of Hypertension, 2020
When distal tubule diuretics are used, there are few, if any, distal compensations, as they act late in the nephron. However, the diluting segment and the high ceiling diuretics both alter the delivery of fluid to the distal nephron which alters the excretion of a variety of substances (Figure 25). In the collecting tubule and collecting duct, sodium is reabsorbed, and potassium and hydrogen ions enter the tubular fluid because of the negative potential difference, which is an electrical force attracting positively charged ions into the lumen. Since the membrane is permeable to potassium and hydrogen ions, these enter the tubule fluid until the electrical force is balanced by the chemical gradient. The size of the potential difference has an important effect on the amount of positively charged ions which enter the lumen. The membrane is less permeable to anions other than chloride, and if these are present, a more negative potential difference develops, with a resulting increase in the loss of potassium and hydrogen ions. This situation is induced by carbonic anhydrase inhibitors, and since most thiazide diuretics are weak inhibitors of carbonic anhydrase, thiazides induce potassium loss by this mechanism. The second factor which makes the potential difference more negative is a high concentration of aldosterone.47 Most diuretics induce an increased secretion of aldosterone, and this also increases potassium loss.
Genetic Basis of Blood Pressure and Hypertension
Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei in Manual of Hypertension of the European Society of Hypertension, 2019
Vascular volume is a primary determinant of arterial pressure over the long term, and sodium acts as the principal determinant of extracellular fluid volume. Epidemiologic studies have linked dietary NaCl intake with HTN (45,46), with non-chloride salts of sodium having little or no effect on BP (47,48). Sodium homeostasis is maintained primarily by the kidneys. The renal glomeruli of a 70-kg man filter ∼25,000 mEq of Na+ and 180 L of water per day, and 99–100% of this amount is reabsorbed in different segments of the nephron – proximal convoluted tubule (60%), the thick ascending limb of the Henle loop (30%), the distal convoluted tubule (7%) and the connecting and the collecting duct (0–3%, controlled by aldosterone and angiotensin-2) (49), pointing to the critical role of the kidneys in sodium balance.
(Zebra)fishing for nephrogenesis genes
Published in Tissue Barriers, 2023
Brooke E. Chambers, Nicole E. Weaver, Caroline M. Lara, Thanh Khoa Nguyen, Rebecca A. Wingert
After passage through the glomerulus, the filtrate then transits to the nephron tubule, which in humans is compartmentalized into a series of proximal, intermediate (or loop of Henle), and distal segments which join to a collecting duct.14 Each segment expresses a unique molecular signature defined by distinct solute transporters and tight junction proteins.15 The proximal convoluted tubule (PCT or S1-S2 segments) and the proximal straight tubule (PST, which most closely corresponds to the S3 segment) perform the bulk of the reabsorption activities and undergo transepithelial transport of glucose, solutes, amino acids, and low molecular weight proteins.16,17 Collectively, proximal tubule cells also play a major role in regulating acid–base balance by reabsorption of bicarbonate.16,17 Another role unique to the proximal tubules involves glucose reabsorption via sodium-glucose cotransporters (SGLT).16,17 Specifically, the PCT expresses SGLT2, and the PST expresses SGLT1, which are encoded by SLC5A2 and SLC5A1, respectively.18–21 In terms of ultrastructure, the PCT cells have a wider brush borders, denser microvilli, and more endocytic vesicles as compared to PST cells.16,17
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
Under normal physiological conditions, blocking sodium transport in the proximal tubule increases distal tubular load and promotes a compensatory enhancement of sodium, chloride, and potassium reabsorption at the loop of Henle primarily by Na-K-2Cl (NKCC2) cotransporters. However, owing to the natriuretic-diuretic coupling effect of SGLT2 inhibition at the proximal tubule, it has been postulated that a diluted load with a low chloride concentration is delivered to the distal nephron and renders tubular reabsorption at the loop of Henle ineffective (Figure 3) [96]. Specifically, since the proximal tubule is highly permeable to water and SGLT2 inhibition renders glucose non-resorbable, isotonicity between the tubular fluid and blood is maintained by osmoregulation. The resulting diuresis is thought to decrease the chloride ion concentration in the proximal tubular filtrate [92]. Therefore, it is speculated that the requirement of two chloride ions for each cotransport at the thick ascending limb subsequently reduces NKCC2 cotransporter activity in a diluted chloride environment [92,96]. The off-target impact of SGLT2 inhibitors at the thick ascending limb may indicate similar activity to that of a loop diuretic to promote plasma volume contraction, although this effect has yet to be proven [96].
Effects of contralateral nephrectomy timing and ischemic conditions on kidney fibrosis after unilateral kidney ischemia-reperfusion injury
Published in Renal Failure, 2022
Junhua Zhang, Ruihua Shen, Hui Lin, Juan Pan, Xinyuan Feng, Ling Lin, Dan Niu, Yanjuan Hou, Xiaole Su, Chen Wang, Lihua Wang, Xi Qiao
According to HE staining, the kidney tissue structure of the mice in the sham group was normal. Compared with the sham group, the 21 min group and 24 min group had pathological changes in varying degrees, including tubular epithelial cell vacuolar degeneration, brush border detachment, focal disintegration necrosis, dilatation of some tubular lumen, kidney tubular epithelial cell edema with variable morphology, wrinkled and sclerotic glomeruli, mesangial cell hyperplasia and dilated Bowman’s capsule, and inflammatory cell infiltration in the interstitial (Figure 9(A)). Pathological injury scores of kidney tubules and glomeruli were significantly higher in both the 21 min and 24 min groups compared with the sham group (p < 0.05), indicating that significant kidney pathological injury developed in both uIRI groups. Furthermore, the 24 min group had higher kidney pathological injury scores and more severe pathological injury compared with the 21 min group (p < 0.05) (Figure 9(B,C)), suggesting that kidney pathological kidney injury had significant changes with a 3 min difference in ischemic duration. The longer the duration of ischemia, the more severe the pathological damage of the kidney.
Related Knowledge Centers
- Kidney
- Renal Corpuscle
- Capillary
- Glomerulus
- Bowman'S Capsule
- Epithelium
- Lumen
- Endothelium
- Basement Membrane
- Podocyte