The role played by endocytosis in albumin-induced secretion of TGF-β₁by proximal tubular epithelial cells

Abstract

Proteinuria predicts the decline of renal function in chronic kidney disease. Reducing albuminuria has been shown to be associated with a reduction in this rate of decline. Proximal tubular epithelial cells (PTECs), when exposed to albumin produce matrix proteins, proinflammatory and profibrotic cytokines like TGF-beta(1). Some of these effects are dependent on endocytosis of albumin by PTECs. However, conditions like diabetic nephropathy, believed to be associated with reduced albumin endocytosis, are associated with interstitial fibrosis. Moreover, megalin, the putative albumin binding receptor in PTECs, has potential signaling motifs in its cytoplasmic domain, suggesting its ability to signal in response to ligand binding from the apical surface of PTECs. Hence, we looked to see whether albumin-induced secretion of TGF-beta(1) by PTECs is dependent on albumin endocytosis or whether it could occur in the absence of albumin endocytosis. We studied the production of TGF-beta(1) in two accepted models of PTECs, opossum kidney cells and human kidney cell clone-8 cells, with widely varying degrees of endocytosis. We then studied the effect of inhibiting albumin endocytosis with various inhibitors on albumin-induced TGF-beta(1) secretion. Our results indicate that albumin-induced TGF-beta(1) secretion by PTECs does not require albumin endocytosis and therefore the mechanism for the induction of some profibrotic responses by albumin may differ from those required for some of the inflammatory responses. Moreover, we found that albumin-induced TGF-beta(1) secretion by PTECs is not dependent on its interaction with megalin.

How Does Proteinuria Cause Progressive Renal Damage?

“…Finding that albumin caused an increase in the levels of tissue inhibitors of metalloproteinases 1 (TIMP-1) and TIMP-2 suggested that a decrease in degradation rather than an increase in protein expression could be responsible for the increased accumulation of extracellular matrix protein components in response to albumin load. Recent findings suggested that dose-dependent TGF-␤ secretion by proximal tubular cells that were exposed to albumin requires activation of mitogen-activated protein kinase signaling pathway upon albumin binding to surface receptors (96). The response would be independent of albumin endocytosis, because inhibitors of endocytosis such as simvastatin and the megalin ligand, receptor-associated protein, failed to inhibit albumin-induced TGF-␤ secretion.…”

The relationship between the TGF-β1 gene −509C/T polymorphism and tubulointerstitial damage resulting from primary nephrotic syndrome

“…These associations indicate that it could be used to predict the progression of chronic renal failure. 5 Furthermore, some investigators found that the CT genotype of the TGF-b1 gene −509C/T was positively correlated with reflux nephropathy. 19 In a longitudinal study of the correlation between the TGF-b1 gene −509C/T polymorphism and IgA nephropathy, Lim et al 20 observed 108 cases for more than 3 years and compared them with 55 healthy adults.…”

“…Numerous studies have also demonstrated that transforming growth factor (TGF)-b1 is the main cytokine leading to glomerulosclerosis and interstitial fibrosis 4 and that the expression of TGF-b1 in kidney tissue can be promoted by urinary protein filtration across the glomeruli. 5 However, TGF-b1 gene polymorphism contributes to the transcription level of TGF-b1 mRNA, as well as to the activation and serum secretion of TGF-b1 protein. Such polymorphism might therefore be useful as markers of progression of renal function failure.…”

Tubular injury in multiple myeloma

“…Megalin siRNA knockdown also had dramatic effects on cubilin levels, into the same degree as knocking down cubilin (38,39,(41)(42)(43)(44).…”

“…Moreover, it is well established that simultaneous silencing of both the cubilin and megalin genes, however, resulted in near-complete inhibi-tion of light chain endocytosis, as determined by measuring kappa-light chain concentration in cell cytoplasm and by flow cytometry (39)(40)(41)(42)(43). Also, light chain-induced cytokine responses (interleukin-6 and monocyte chemoattractant protein-1) and epithelial-to-mesenchymal transition, as well as the associated cellular and morphological alterations were also markedly suppressed (39,40,44).…”