Renal expression of advanced oxidative protein products predicts progression of renal fibrosis in patients with IgA nephropathy.

Predicting the risk of disease progression in IgA nephropathy (IgAN) remains a challenge. This study was conducted to test the hypothesis that renal accumulation of advanced oxidized protein products (AOPPs) is an early predictor for renal progression in IgAN. This was a single-center prospective cohort study. One hundred IgAN patients with eGFR>80 ml/min/1.73 m(2) were enrolled. Seventy-seven patients were followed for a mean of 4.2 years, and 30 patients received repeat renal biopsy at a mean of 42 months after diagnosis. The outcomes were the progression of renal fibrosis and rapid progression of CKD (>5 ml/min/1.73 m(2)/year) during follow-up. Immunoreactivity of AOPPs was detected predominantly in tubular epithelial cells and co-localized with expression of TGF-ß1 and angiotensin II. Renal staining score of AOPPs at diagnosis was associated with the level of tissue cellular inflammation. Accumulation of AOPPs, particularly in interstitial-infiltrating cells, was negatively correlated with changes of eGFR during follow-up; those with expression scores greater than the median at diagnosis had significantly higher incidences of rapid decline of eGFR compared with those with the score less than or equal to the median. For patients who received repeat renal biopsy, renal AOPP levels greater than the median at diagnosis were associated with increase in renal fibrosis index at repeat biopsy. After multivariate adjustment, renal AOPP expression was an independent predictor for progression of renal fibrosis and rapid decline of eGFR. Taken together, these results demonstrate that renal AOPPs might be a predictor, detectable at the time of diagnosis, for renal progression in patients with early stage IgAN.

Albumin overload activates intrarenal renin-angiotensin system through protein kinase C and NADPH oxidase-dependent pathway.

OBJECTIVE: Inappropriate activation of the intrarenal renin-angiotensin system (RAS) plays an important role in the pathogenesis of hypertension and renal injury. However, the underlying mechanisms remain elusive. Proteinuria has been shown to elicit the renal activation of RAS. The present study was performed to test the intracellular signal pathway involved in albumin-triggered activation of RAS. DESIGN AND METHODS: NRK52E cells, a rat renal proximal tubular cell line, were incubated with increased levels of albumin. The rat model of protein overload was established in female Wistar-Kyoto rats that were subjected to unilateral nephrectomy followed by daily intraperitoneal injection of BSA at various doses (0.5, 1.0, and 5.0 g/kg) or combination with intragastric administration of apocynin (100 mg/kg per day), an inhibitor of NADPH oxidase. RESULTS: Exposure of the cells to high levels of albumin activated the RAS through the endocytic receptors megalin and cubilin. High levels of albumin triggered the production of intracellular reactive oxygen species by a protein kinase C (PKC)-NADPH oxidase-dependent pathway and this, in turn, led to activation of nuclear factor-κB (NF-κB) and activation protein-1 (AP-1). Inhibition of PKC or NADPH oxidase abolished albumin-induced activation of RAS. In a protein overload rat model, activation of RAS in renal proximal tubular cells was significantly increased, coincident with activation of PKC, NADPH oxidase, NF-κB, and AP-1. Chronic inhibition of NADPH oxidase by apocynin largely ameliorated intrarenal activation of RAS. CONCLUSION: Exposure of renal tubular epithelial cells with high levels of albumin triggers activation of RAS via a PKC-NADPH oxidase-dependent pathway.