PKB is a central molecule in the modulation of Na+-ATPase activity by albumin in renal proximal tubule cells

Evidence points to a possible role of tubular sodium reabsorption in worsening renal injury. Proximal tubule (PT) albumin overload is a critical process in the development of tubule-interstitial injury (TII), and consequently in progression of renal disease. We studied the possible correlation betwe...

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Published in:	Archives of biochemistry and biophysics Vol. 674; p. 108115
Main Authors:	Peruchetti, Diogo B., Freitas, Andreson C., Pereira, Vitor C., Lopes, Juliana V., Takiya, Christina M., Nascimento, Nilberto R.F., Pinheiro, Ana Acacia S., Caruso-Neves, Celso
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 15-10-2019
Subjects:	Adenosine Triphosphatases - metabolism Albumin overload Albuminuria Animals Cation Transport Proteins - metabolism Cattle Cell Line Extracellular Signal-Regulated MAP Kinases - metabolism Kidney Tubules, Proximal - cytology Male Mechanistic Target of Rapamycin Complex 1 - metabolism Protein kinase B Proto-Oncogene Proteins c-akt - metabolism Rats, Wistar Renal disease Renal sodium excretion Ribosomal Protein S6 Kinases - metabolism Serum Albumin, Bovine - metabolism Signal Transduction - physiology Sodium pump Sodium-Potassium-Exchanging ATPase - metabolism Swine Renal sodium excretion Renal disease Albumin overload Sodium pump Protein kinase B Albuminuria
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Summary:	Evidence points to a possible role of tubular sodium reabsorption in worsening renal injury. Proximal tubule (PT) albumin overload is a critical process in the development of tubule-interstitial injury (TII), and consequently in progression of renal disease. We studied the possible correlation between changes in albumin concentration in the lumen of PT with modification of Na+-ATPase activity. An albumin overload animal model and LLC-PK1 cells as a model of PT cells were used. Albumin overload was induced by intraperitoneal injection of BSA in 14-week-old male Wistar rats. An increase in sodium clearance, fractional excretion of sodium, proteinuria, ratio between urinary protein and creatinine, and albuminuria were observed. These observations indicate that there could be a correlation between an increase in albumin in the lumen of PTs and renal sodium excretion. We observed that the activity of both Na+-ATPase and (Na++K+)ATPase decreased in the renal cortex of an albumin overload animal model. Using LLC-PK1 cells as a model of PT cells, inhibition of Na+-ATPase activity was observed with higher albumin concentrations, similar to that observed in the animal model. The inhibition of protein kinase B by higher albumin concentration was found to be a critical step in the inhibition of Na+-ATPase activity. Interestingly, activation of the ERK1/2/mTORC1/S6K pathway was required for protein kinase B inhibition. This mechanism leads to a decrease in protein kinase C activity and, consequently to inhibition of Na+-ATPase activity. Taken together, our results indicate that the molecular mechanism underlying the modulation of PT Na+-ATPase activity by albumin overload involves activation of the ERK1/2/mTORC1/S6K pathway, which leads to inhibition of the mTORC2/PKB/PKC pathway. Our findings contribute to better understanding regarding handing of renal Na+ induced by albumin overload in the lumen of PTs and, consequently, in the progression of renal disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0003-9861 1096-0384
DOI:	10.1016/j.abb.2019.108115