Year-end Sale % OFF 
Abstract
Albuminuria promotes tubular injury and cell death, and is associated with faster progression of chronic kidney disease (CKD) to end-stage renal disease. However, the molecular mechanisms regulating tubular cell death in response to albuminuria are not fully understood. Brain abundant signal protein 1 (BASP1) was recently shown to mediate glucose-induced apoptosis in tubular cells. We have studied the role of BASP1 in albumin-induced tubular cell death. BASP1 expression was studied in experimental puromycin aminonucleoside-induced nephrotic syndrome in rats and in human nephrotic syndrome. The role of BASP1 in albumin-induced apoptosis was studied in cultured human HK2 proximal tubular epithelial cells. Puromycin aminonucleoside induced proteinuria and increased total kidney BASP1 mRNA and protein expression. Immunohistochemistry localized the increased BASP1 to tubular cells. BASP1 expression colocalized with deoxynucleotidyl-transferase-mediated dUTP nick-end labeling staining for apoptotic cells. Increased tubular BASP1 expression was observed in human proteinuric nephropathy by immunohistochemistry, providing evidence for potential clinical relevance. In cultured tubular cells, albumin induced apoptosis and increased BASP1 mRNA and protein expression at 6–48 h. Confocal microscopy localized the increased BASP1 expression in albumin-treated cells mainly to the perinuclear area. A peripheral location near the cell membrane was more conspicuous in albumin-treated apoptotic cells, where it colocalized with actin. Inhibition of BASP1 expression by a BASP1 siRNA protected from albumin-induced apoptosis. In conclusion, albumin-induced apoptosis in tubular cells is BASP1-dependent. This information may be used to design novel therapeutic approaches to slow CKD progression based on protection of tubular cells from the adverse consequences of albuminuria.
Highlights
Apoptosis is an active response to an altered microenvironment characterized by the activation of specific intracellular lethal pathways.[17]
Cell culture studies identified a high glucose concentration as an inducer of BASP1 expression and BASP1-dependent apoptosis. This cell culture observation does not explain the patchy distribution of BASP1-expressing tubules in human diabetic kidney, as all tubules would have been exposed to the same high glucose concentrations
Systemic puromycin aminonucleoside (PAN) administration causes podocyte injury in rats leading to an increased urinary protein excretion at day 2 and full-blown nephrotic syndrome characterized by severe albuminuria (Figure 1a), hypoalbuminemia, hypercholesterolemia and ascites at day 10
Summary
Apoptosis is an active response to an altered microenvironment characterized by the activation of specific intracellular lethal pathways.[17]. As albumin induces apoptosis in cultured tubular cells,[10,11,12] we hypothesized that albumin could be an inducer of BASP1 expression in tubular cells This hypothesis might explain the observation of BASP1-positive and -negative tubules in human diabetic nephropathy and experimental diabetic and hypertensive nephropathies.[19] Tubules belonging to a nephron where podocyte injury has resulted in glomeruloesclerosis and more severe albuminuria would be expected to express more BASP1 than tubules from nephrons with more preserved functional podocytes. To explore this hypothesis, we used cell culture and non-diabetic albuminuria models. This information may be used to protect the tubulointerstitium from structural damage in proteinuric kidney diseases with residual albuminuria despite anti-proteinuric therapy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
