Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein.

Abstract

Cytokines play a pivotal role in synthesis and deposition of extracellular matrix in chronic renal failure (CRF). The proinflammatory properties of monocyte chemoattractant protein (MCP)-1 make it an ideal candidate cytokine for the production of interstitial inflammation in CRF. To investigate the possible role of proteinuria in inducing proximal tubular (PT) MCP-1, MCP-1 mRNA levels were measured by Northern blot and reverse transcription PCR in confluent monolayers of PT cells in primary culture in media containing a variety of proteins. PT cells produced MCP-1 mRNA in response to bovine serum albumin (BSA), delipidated BSA (dBSA; 0.5 to 30 mg/ml), holotransferrin, and apotransferrin (1 to 8 mg/ml). Unstimulated PT cells expressed very low levels of MCP-1 mRNA, detectable by reverse transcription PCR but not by Northern blot. The expression of MCP-1 mRNA reached a peak (sixfold greater than control) within 4 h of exposure to dBSA and was maintained for at least 24 h with continued exposure. Removal of dBSA from the media led to a rapid decline in MCP-1 mRNA expression. dBSA-induced MCP-1 expression was inhibited by lysine, an inhibitor of protein uptake, and reproduced by dBSA purified by gel and size-selective filtration. dBSA influenced MCP-1 expression at the level of transcription and probably translation, as evidenced by abrogation of MCP-1 by actinomycin D and superinduction with the protein synthesis inhibitor cycloheximide. The concentration of MCP-1 protein in response to dBSA added to the apical surface of PT cells was 2.4-fold greater in basolateral than in apical media, indicating basolateral secretion of MCP-1 protein. In summary, PT cell MCP-1 mRNA and protein expression are upregulated by albumin and transferrin, in concentrations similar to those of proteinuric urine. This effect could explain the link between proteinuria and interstitial inflammation in CRF.

Enhanced MCP-1 Release in Early Autosomal Dominant Polycystic Kidney Disease

“… 49 It has been demonstrated that albumin uptake and overload of albumin endocytosis in the proximal tubules lead to interstitial inflammation and infiltration of inflammatory cells via upregulation of proinflammatory cytokines such as MCP-1. 50 , 51 Increased albumin exposure of proximal tubular cells in ADPKD might be an additional (third-hit) driver for MCP-1 production in tubular cells in more advanced disease stages, as could be tubular crystal deposition. 52 None of these potential mechanisms are mutually exclusive.…”

Markers of kidney tubular and interstitial injury and function among sugarcane workers with cross-harvest serum creatinine elevation

“…The choice of this particular set of markers was determined by this set being available for analysis using a single multiplex assay (Bio-Plex Pro RBM Kidney Toxicity Panel I) consisting only of tubular injury biomarker assays. MCP-1 and KIM-1 are elevated in primarily proximal tubular injury24 25 and have been linked to biopsy-verified tubulointerstitial fibrosis and progression of kidney disease 26 27. Calbindin and GST-π are primarily expressed in the distal tubuli,28 29 but their association with long-term outcomes is less well understood.…”

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

“…Albumin is known to cause PT stress, injury, interstitial cell infiltration, and fibrosis through a large number of cellular toxicity pathways ( 129 ). These pathways include complement activation, chemokine expression, NF-κB-dependent and -independent pathways ( 130 , 131 ), oxidative stress with superoxide generation via NAPDH oxidase activation with subsequent generation of H 2 O 2 and multiple intracellular pathways ( 132 , 133 ), type II TGF-β upregulation ( 134 ), endoplasmic reticulum (ER) stress with caspase 12 activation and apoptotic cell death ( 135 ), dysfunctional autophagy ( 136 ), inflammasome activation ( 137 ), delivery of nonesterified fatty acids by excess filtered albumin resulting in apoptosis ( 138 ), and Klotho downregulation leading to increased FGF 23 expression ( 139 ). Zoja et al ( 140 ) have reviewed this topic and offer an integrated approach, yet what remains to be determined is exactly what is leading to the toxicity of urinary proteins and in particular albumin.…”