HORMONES - CYTOKINES - SIGNALING Pioglitazone increases renal tubular cell albumin uptake but limits proinflammatory and fibrotic responses

Zafiriou, Stephen; Stanners, Scott R.; Polhill, Tania S.; Poronnik, Philip; Pollock, Carol A.
May 2004
Kidney International;May2004, Vol. 65 Issue 5, p1647
Academic Journal
Pioglitazone increases renal tubular cell albumin uptake but limits proinflammatory and fibrotic responses. Background. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists, which are known to be critical factors in lipid metabolism, have also been reported to reduce proteinuria. The mechanism and its relevance to progressive nephropathy have not been determined. The aims of this study were to assess the direct effects of a PPARγ agonist on tubular cell albumin uptake, proinflammatory and profibrotic markers of renal pathology, using an opossum kidney model of proximal tubular cells. Methods. Cells were exposed to pioglitazone (10 μmol/L) in the presence and absence of low-density lipoprotein (LDL) 100 μg/mL ± exposure to albumin 1 mg/mL. Results were expressed relative to control (5 mmol/L glucose) conditions. Results. Pioglitazone caused a dose-dependent increase in tubular cell albumin uptake ( P < 0.0001). Despite the increase in albumin reabsorption, no concurrent increase in inflammatory or profibrotic markers were observed. Exposure to LDL increased monocyte chemoattractant protein-1 (MCP-1) ( P < 0.05) and transforming growth factor-β1 (TGF-β1) ( P < 0.05) production, which were reversed in the presence of pioglitazone. LDL induced increases in MCP-1 and TGF-β1 were independent of nuclear factor-κB (NF-κB) transcriptional activity. In contrast, tubular exposure to albumin increased tubular protein uptake, in parallel with an increase in MCP-1 ( P= 0.05), TGF-β1 ( P < 0.02) and NF-κB transcriptional activity ( P < 0.05), which were unaffected by concurrent exposure to pioglitazone. Conclusion. These findings suggest that dyslipidemia potentiates renal pathology through mechanisms that may be modified by PPARγ activation independent of NF-κB transcriptional activity. In contrast, tubular exposure to protein induces renal damage through NF-κB–dependent mechanisms that are unaffected by PPARγ activation.


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