Search

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no existing therapeutic approach to delay or stop progression. Genetic, biochemical and pre-clinical studies have provided evidence that leucine-rich-repeat-kinase-2 (LRRK2) kinase is involved in the pathogenesis of PD, and small molecule LRRK2 inhibitors represent a novel potential therapeutic approach. However, potentially adverse target-related effects have been discovered in the lung and kidneys of LRRK2 knock-out (ko) mice and rats. It is unclear if the LRRK2 ko effect in the kidneys and lung is also induced by pharmacological inhibition of the LRRK2 kinase. Here, we show that treatment with the LRRK2 inhibitor PFE-360 in rats induces a morphological kidney phenotype resembling that of the LRRK2 ko rats, whereas no effects were observed in the lung. The PFE-360 treatment induced morphological changes characterised by darkened kidneys and progressive accumulation of hyaline droplets in the renal proximal tubular epithelium. However, no histopathological evidence of renal tubular injury or changes in the blood and urine parameters that would be indicative of kidney toxicity or impaired kidney function were observed after up to 12 weeks of treatment. Morphological changes were detected in the kidney after 2 weeks of treatment and were partially reversible within a 30 day treatment-free period. Our findings suggest that pharmacological LRRK2 inhibition may not have adverse consequences for kidney function., (Copyright © 2018 H. Lundbeck A/S. Published by Elsevier B.V. All rights reserved.)

The kidney is the most important excretory organ in the body and plays an essential role in maintaining homeostasis in vivo by conserving body fluid and electrolytes and removing metabolic waste. In this study, three types of transgenic system were used to investigate the expression of the bitter taste receptor Tas2r105 in mouse renal tissue (Tas2r105-GFP/Cre, Tas2r105-GFP/Cre-DTA and Tas2r105-GFP/Cre-LacZ). The results suggest that bitter taste receptors Tas2r105 and Tas2r106 are expressed in the renal corpuscle and the renal tubule, including the proximal tubule and distal tubule. Expression of α-gustducin, an important component of taste signal transduction, was also detected in mouse kidney. Meanwhile, conditional diphtheria toxin (DTA) expression in Tas2r105+ cells caused an increase in size of the glomerulus and renal tubule, accompanied by a decrease in cell density in the glomerulus. This indicates that Tas2r105+ cells play an important role in maintaining the structure of the glomerulus and renal tubules. Overall, the current study collectively demonstrates that cells labeled by bitter taste receptor expression may play a critical role in controlling human health, and have properties far beyond the original concept of taste perception., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Proximal tubule (PT) angiotensinogen (AGT) is part of a tubular renin-angiotensin system (RAS) that participates in the regulation of sodium reabsorption along the entire nephron. Physiologic maneuvers affecting AGT expression in PT also affect systemic RAS. Here, we tested the hypothesis that PT AGT is regulated by increased glomerular filtration rate (GFR)., Methods: Complete unilateral nephrectomy (UNX) in mice was used to induce a sustained increase in GFR in the remaining kidney. AGT expression was monitored by quantitative reverse transcription-polymerase chain reaction (RT-PCR). AGT protein in PT was investigated by semiquantitative histology. We also measured AGT concentration in plasma and in 24-hour urine by a specific enzyme-linked immunosorbent assay (ELISA)., Results: Seven weeks after nephrectomy, UNX animals exhibited a 2-fold increase in tubular AGT mRNA (P <.001) compared with sham-operated control animals. The proportion of PT sections exhibiting AGT immunostaining was significantly increased at day 3 (P <.05), and remained elevated at seven weeks (UNX = 0.63 +/- 0.09, sham = 0.38 +/- 0.02, P <.01), revealing recruitment of AGT-producing cells along the PT. AGT excretion in final urine corrected for creatinine and kidney weight was also elevated by UNX at seven weeks (UNX = 209 +/- 42 pmol/mg/g, sham = 147 +/- 29 pmol/mg/g, P <.05), with no difference in plasma AGT between UNX and control animals., Conclusion: These observations suggest that AGT expression in PT adapts in the long-term to changes in GFR. In the UNX model, urinary AGT excretion is also elevated as a consequence of increase in net tubular flow.

The subcellular distribution and segmental variations in location of gp330, a scavenger receptor for filtered proteins in renal proximal tubules, was analyzed. Kidney tissue from rats (4 different strains), rabbits and humans were analyzed by light- and electron microscope immunocytochemistry, using cryosections or Lowicryl sections from cryosubstituted tissue. Gp330 was located mainly in apical coated pits, small and large endocytic vacuoles and in dense apical tubules in the proximal tubule cells. The labeling density was markedly higher in segments 1 and 2 as compared to segment 3 of the proximal tubule. In addition to the location in the early part of the endocytic pathway, gp330 was also present in lysosomes, especially in segments 1 and 2. The lysosomal labeling was not restricted to the membrane, but was also seen in the matrix. Localization of gp330 in lysosomes was confirmed on sections from purified lysosomal fractions from rat renal cortex. The brush border localization of gp330 in proximal tubules exhibited a characteristic segmental variation. In the initial part of segment 1, there was virtually no brush border labeling. In the remaining part of segment 1 and in segment 2, there was a distinct but sometimes patchy labeling of the brush border. In segment 3, groups of microvilli of approximately 10 as seen in sections were intensively labeled from bottom to tip and there were often more than one of these groups on a single cell, the remaining microvilli were unlabeled. No differences in the cellular and subcellular localization of gp330 were observed between species or rat strains. In conclusion, the present study demonstrates that in addition to its location in the early endocytic and recycling pathway, gp330 is also present in microvilli and the protein and degradation products thereof is present in lysosomes, consistent with its role as a protein scavenger receptor.

Previous research in animals and humans has demonstrated that many nephrotoxic chemicals induce selective injury within the kidney affecting either renal proximal straight (PST) or proximal convoluted (PCT) tubules. Selective injury has also been observed following in vitro nephrotoxicant exposure to precision-cut renal slices and isolated PCT and PST segments. These in vitro models provide a means of comparing and contrasting basic mechanistic differences which render these segments innately susceptible to nephrotoxicant injury. In this article, methods for preparing precision-cut slices and isolating PST and PCT segments will be reviewed.

The present studies tested the hypothesis that osmotic disequilibrium between luminal and peritubular fluids is the driving force for net volume absorption in the isolated proximal straight tubule. Isolated tubule segments from superficial rabbit renal cortex were perfused at varying rates with a high chloride and bicarbonate-free solution as they were bathed with a normal bicarbonate-Krebs-Ringer buffer solution at 38 degrees C. Increasing the perfusion rate from congruent to 4 to congruent to 30 nl/min produced a monotonic increase in net volume absorption (Jv) from 0.18 +/- (sem) 0.03 to 0.62 +/- 0.08 nl . min-1. The chloride concentration in collected fluid samples rose from congruent to 137 to congruent to 147 mEq/liter over the same perfusion rate range. Ouabain (10(-4) m) added to the bathing solution inhibited Jv by a rate which varied from 0.20 to 0.28 nl . min-1 . min-1, depending on the perfusion rate. A mathematical model of the axial flows and transepithelial transport processes was developed. This model, and the experimental data, is consistent with the view that the driving force for isotonic fluid absorption in these tubules depends on the axial maintenance of osmotic disequilibrium between the perfusate and the bathing solution. Increasing the perfusion rate opposes osmotic equilibration by minimizing the extent to which dissipative fluxes of chloride and bicarbonate ions change the transepithelial chloride and bicarbonate concentration gradients, and by minimizing the tendency of the luminal cryoscopic osmolality to increase as volume absorption occurs.

Effects of parathyroid hormone (PTH), calcitonin (CT), vasopressin (VP), and glucagon (GL) on adenylate cyclase activity and cyclic AMP (cAMP) levels in isolated cortical thick ascending limbs of Henle's loop (CTAL) of the rat kidney were examined. PTH, CT, and VP each stimulated adenylate cyclase of this nephron segment in a dose-dependent manner. Stimulation of the enzyme activity was greatest with a maximal dose of PTH and least with VP. With maximal doses, the effects of PTH and CT were not additive; whether or not the effects of maximal doses of VP and PTH or CT were additive was not clear. All three hormones increase cAMP in intact CTAL ina dose-dependent manner. Maximal doses of PTH, CT, VP, and GL resulted in comparable rises in cell cAMP, and there was no additive effect. These data suggest that PTH and CT may stimulate the same adenylate cyclase moieties, whereas VP may stimulate distinct enzyme moieties, and that these three peptide hormones as well as GL definitely act on the same cell group in rat CTAL. Thus, it is possible that these hormones may induce qualitatively similar effects on CTAL functions if such effects are mediated by cAMP.