Biomedical subjects

Carla Zoja

Publications and source records attributed to Carla Zoja.

22 records · Page 2Linked to original sources

PubMed2002

How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach.

The current therapy for chronic proteinuric nephropathies is angiotensin-converting enzyme inhibitors (ACEi), which slow, but may not halt, the progression of disease, and which may be not effective to the same degree in all patients. In accelerated passive Heymann nephritis (PHN), this study assessed the effect of combining ACEi with angiotensin II receptor antagonist (AIIRA) and with statin that, besides lowering cholesterol, influences inflammatory and fibrogenic processes. Uninephrectomized PHN rats were divided into four groups (n = 10 each) and daily given oral doses of the following: vehicle; 40 mg/L lisinopril; 100 mg/L lisinopril plus L-158,809; 0.3 mg/kg lisinopril plus L-158,809 plus cerivastatin. Treatments started at 2 mo when rats had massive proteinuria and signs of renal injury and lasted until 10 mo. Increases in BP were equally lowered by treatments. ACEi kept proteinuria at levels comparable to pretreatment and numerically lower than vehicle. The addition of AIIRA to lisinopril was more effective, being proteinuria reduced below pretreatment values and significantly lower than vehicle. When cerivastatin was added on top of ACE inhibition and AIIR blockade, urinary protein regressed to normal values and renal failure was prevented. Renal ACE activity was increased threefold in PHN, it was inhibited by more than 60% after ACEi, and decreased below control values with triple therapy. Cerivastatin inhibited ACE activity by 30%. Glomerulosclerosis, tubular damage and interstitial inflammation were ameliorated by ACEi alone or combined with AIIRA, and prevented by addition of statin. TGF-beta(1) mRNA upregulation in PHN kidney was partially reduced after ACEi or combined with AIIRA and almost normalized after adding statin. Cerivastatin inhibited TGF-beta(1) gene upregulation by 25%. These data suggest a possible future strategy to induce remission of proteinuria, lessen renal injury, and protect from loss of function in those patients who do not fully respond to ACEi therapy.

Angiotensin Receptor Antagonists↗

PubMed2002

Protein overload-induced NF-kappaB activation in proximal tubular cells requires H(2)O(2) through a PKC-dependent pathway.

Abnormal traffic of proteins through the glomerular capillary has an intrinsic toxicity that results in tubular dysfunction and interstitial inflammation. It has been previously shown that in porcine proximal tubular cells high concentrations of albumin activated NF-kappaB, which is responsible for the enhanced synthesis of the inflammatory chemokine RANTES. This study investigates whether reactive oxygen species (ROS) served as second messengers in protein overload-induced NF-kappaB activation. Human proximal tubular cells (HK-2) were incubated (5 to 60 min) with human albumin and IgG (1 to 30 mg/ml). Both proteins induced a rapid or significant increase in hydrogen peroxide (H(2)O(2)) production at 5 min and persisting at 60 min. This effect was dose-dependent. The contribution of H(2)O(2) in regulating NF-kappaB activation was evaluated by using the antioxidants dimethyl-thiourea and pyrrolidine dithiocarbamate in protein-overloaded HK-2 cells. Both agents, by preventing H(2)O(2) generation, induced human albumin or IgG inhibited NF-kappaB activation. Stimulation of HK-2 with exogenous H(2)O(2) resulted in the activation of a NF-kappaB subunit pattern similar to that obtained after protein challenge. Specific inhibitors of protein kinase C (PKC) activity significantly prevented H(2)O(2) production and consequent NF-kappaB activation, suggesting that ROS generation in HK-2 cells occurs downstream of PKC activation. Either antioxidants or PKC inhibitor almost completely abolished the upregulation of the monocyte chemoattractant protein-1 gene induced by excess albumin, as evaluated by real-time PCR, thus supporting a role for PKC and ROS as critical signals for the expression of NF-kappaB-dependent inflammatory genes. To identify the enzymatic sources responsible for the increased H(2)O(2) production, the effect of dyphenyleneiodonium, an inhibitor of the membrane NADP(H) oxidase, was studied, as was the effect of rotenone, which blocks complex I of the mitochondrial respiratory chain. It was found that both agents significantly reduced the exaggerated H(2)O(2) induced by protein overload. These data indicate that exposure to excess proteins in proximal tubular cells induces the formation of ROS, which are responsible for NF-kappaB activation and consequent induction of NF-kappaB-dependent inflammatory signals.

Analysis of Variance↗

PubMed2001

Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis.

Angiotensin-converting enzyme inhibitors restore size-selective dysfunction of the glomerular barrier in experimental animals and humans with proteinuric nephropathies, although the structural and molecular determinants of such an effect are not completely understood. This study used an accelerated model of experimental nephrosis to assess nephrin gene and protein expression in the kidney and the possible modulating effect of drugs that block angiotensin II (AII) synthesis/activity. Passive Heymann nephritis (PHN) and control animals were studied at day 7, month 4, and month 8. Additional PHN rats were treated with lisinopril or AII receptor blocker L-158,809 and studied at 8 mo. Lisinopril and L-158,809 controlled BP, prevented proteinuria, and protected PHN animals from renal injury. An intense signal of nephrin mRNA was detected in glomeruli of control animals mainly restricted to podocytes. In PHN rats, nephrin staining progressively and remarkably decreased with time. Lisinopril and L-158,809 fully prevented the decrease in nephrin transcripts to levels comparable to those of control rats. Consistent with nephrin mRNA expression, immunostaining of the protein showed a progressive decrease in kidneys from PHN rats that was completely abolished by lisinopril and L-158,809. In summary, progressive renal injury was associated with downregulation of nephrin gene that was totally prevented by angiotensin-converting enzyme inhibitor and AII receptor blocker, suggesting that renoprotection afforded by drugs that interfere with AII synthesis/activity was related to an effect on nephrin assembly.

Angiotensin II↗

PubMedDate not supplied

Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR.

TIR8, also known as single Ig IL-1R-related molecule (SIGIRR), is a member of the IL-1 receptor family. The present study was designed to investigate the expression and function of TIR8. TIR8 was mainly expressed in mouse and human epithelial tissues such as kidney, lung and gut. Resting and activated T and B lymphocytes and monocytes-macrophages expressed little or no TIR8, with the exception of the mouse GG2EE macrophage line. In the kidney, the organ with highest mRNA levels, TIR8 expression was confined to epithelial cells and, in situ, to tubular epithelium. A variety of signals failed to regulate TIR8 expression, but LPS reduced TIR8 mRNA transcripts. An NF-kB driven reporter system was used to investigate the function of TIR8. TIR8 did not activate NF-kB expression alone or in concert with IL-1R1. In contrast, TIR8 inhibited signaling from the IL-1R complex. Inhibition required the intracellular portion of TIR8 but the extracellular domain was dispensable for blocking activity. Thus, TIR8 is a unique member of the IL-1R family, with a distinct pattern of epithelial expression, including the kidney and mucosae, and an inhibitory function on IL-1 signaling.

Animals↗