Time‐course of sodium transport along the nephron in nephrotic syndrome: The role of potassium

Abstract

The mechanism of sodium retention and its location in kidney tubules may vary with time in nephrotic syndrome (NS). We studied the mechanisms of sodium retention in transgenic POD-ATTAC mice, which display an inducible podocyte-specific apoptosis. At day 2 after the induction of NS, the increased abundance of NHE3 and phosphorylated NCC in nephrotic mice compared with controls suggest that early sodium retention occurs mainly in the proximal and distal tubules. At day 3, the abundance of NHE3 normalized, phosphorylated NCC levels decreased, and cleavage and apical localization of γ-ENaC increased in nephrotic mice. These findings indicate that sodium retention shifted from the proximal and distal tubules to the collecting system. Increased cleavage and apical localization of γ-ENaC persisted at day 5 in nephrotic mice when hypovolemia resolved and steady-state was reached.Sodium retention and γ-ENaC cleavage were independent of the increased plasma levels of aldosterone. Nephrotic mice displayed decreased glomerular filtration rate and urinary potassium excretion associated with hyperkaliemia at day 3. Feeding nephrotic mice with a low potassium diet prevented hyperkaliemia, γ-ENaC cleavage, and led to persistent increased phosphorylation of NCC. These results suggest that potassium homeostasis is a major determinant of the tubular site of sodium retention in nephrotic mice. K E Y W O R D Saldosterone paradox, edema, ENaC, hyperkalemia, proteinuria, SRAA | 2409 DIZIN et al.

Expanded renal lymphatics improve recovery following kidney injury

“…Increased albuminuria was equivalent across mouse strains, however, in the 7 days following glomerular injury (Figure 2j ). The proteinuric time course was thus similar to previous studies using this model (Dizin et al, 2020 ; Rutkowski et al, 2013 ). The dimerizer agent utilized to induce the caspase‐8 mediated podocyte apoptosis caused no functional effects in wild‐type mice (Figure S1a–f ).…”

“…Another study further supports a beneficial role for intrarenal CD4+ T cell presence and reported that infusion of CD4+CD25+ Tregs at day 1 post‐IRI had a protective role by modulating pro‐inflammatory cytokines (Gandolfo et al, 2009 ). Our study utilized the POD‐ATTAC model, which has been previously reported as a model of focal segmental glomerulosclerosis (FSGS), otherwise known as nephrotic syndrome (Dizin et al, 2020 ; Rutkowski et al, 2013 ). The use of this model provides a genetic tool to investigate progressive renal disease initiated from a one‐time isolated glomerular injury.…”

“…Generation and use of the KidVD mouse line (KSP‐rtTA × TRE‐VEGFD) have been previously described (Lammoglia et al, 2016 ; Lopez Gelston et al, 2018 ). POD‐ATTAC mice have been previously described and employed in injury and nephrotic syndrome studies (Dizin et al, 2020 ; Rutkowski et al, 2013 ). KidVD and POD‐ATTAC hemizygous mice were maintained on a C57/Bl6J lineage and crossed to generate experimental lines.…”

“…Accordingly, in the present study, we hypothesized that an increased renal lymphatic density would be protective following kidney injury. To test this hypothesis, we utilized a transgenic mouse model of kidney‐specific overexpression of VEGF‐D (KidVD) (Balasubbramanian, Baranwal, et al, 2020 ; Balasubbramanian, Gelston, et al, 2020 ; Lammoglia et al, 2016 ; Lopez Gelston et al, 2018 ) and induced renal lymphatic expansion prior to injury in two models of injury to the kidney: the POD‐ATTAC model of induced proteinuria by selective podocyte ablation (Dizin et al, 2020 ; Rutkowski et al, 2013 ) or bilateral renal ischemia‐reperfusion injury (IRI). While the initial extent of injury and functional loss was comparable to wild‐type injured littermates during the acute phase, KidVD mice displayed an altered immune response and decreased fibrosis suggesting a protective role of lymphatic vessel expansion to potentially reduce CKD progression.…”

Rôle du néphron distal dans le contrôle du volume extracellulaire en condition physiologique et dans le syndrome néphrotique

“…Dans ce modèle, le syndrome néphrotique est provoqué par une apoptose inductible des podocytes glomérulaires [37]. Dans ce modèle de syndrome néphrotique, l'étude de la cinétique de la rétention sodée permet d'identifier deux phases : une première phase, pendant laquelle la réabsorption excessive de sodium a lieu dans le tube contourné distal via une activation de NCC ; et une seconde phase, dans laquelle la rétention sodée se situe au niveau du système collecteur via une activation de ENaC [38]. Ce changement de site de rétention sodée est lié à l'apparition d'une hyperkaliémie.…”