Isabella Bruzzi

Proximal tubular cell synthesis and secretion of endothelin-1 on challenge with albumin and other proteins

Abnormal traffic of proteins through the glomerular capillary has an intrinsic renal toxicity possibly linked to the subsequent process of over-reabsorption by proximal tubular cells. We investigated in vitro the effect of different protein concentrations on proximal tubular cell endothelin-1 (ET-1) synthesis. Rabbit proximal tubular RC.SV1 cell line was grown to confluence in serum-free hormonally defined medium. Cells were incubated for 6 and 24 hours with serum-free medium containing bovine serum albumin (BSA, 0.1 to 10 mg/mL). ET-1, a locally released hormone that stimulates cell proliferation and promotes extracellular matrix protein synthesis, was measured in cell supernatant by radioimmunoassay. BSA induced a significant dose-dependent increase in proximal tubular cell ET-1 synthesis. BSA and fatty acid-free BSA stimulated tubular ET-1 synthesis and release to a comparable extent, indicating that the lipid component of the molecule is not involved in the observed phenomenon. Experiments in which tubular cells grown on filters in bicameral systems were incubated with BSA (10 mg/mL) showed that ET-1 release was predominantly basolateral. The stimulatory effect on tubular ET-1 synthesis and release was not specific to albumin but was shared by immunoglobulin (Ig) G and transferrin. Exposure of proximal tubular cells for 6 and 24 hours to both proteins (1 and 10 mg/mL) resulted in a dose-dependent increase in ET-1 synthesis. These data suggest that overexposure of proximal tubular cells to proteins, as it occurs in vivo in proteinuric renal diseases, may promote excessive tubular synthesis of ET-1, which is mostly secreted toward the interstitial compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

Renoprotection by nitric oxide donor and lisinopril in the remnant kidney model.

Previous studies showed a renoprotective effect of l-arginine in experimental uremia. Whether this was caused by an increased nitric oxide (NO) release or depended on l-arginine per se is not clear. Here, we evaluated whether chronic administration of an NO donor, molsidomine, controlled systemic blood pressure and renal disease progression and prolonged survival in rats with renal mass reduction (RMR). Rats with RMR received the following daily in the drinking water: group 1 (n = 21), no specific therapy (vehicle); group 2 (n = 12), molsidomine, 120 mg/L; group 3 (n = 9), lisinopril, 25 mg/L; and group 4 (n = 12), reserpine, 5 mg/L, hydralazine, 80 mg/L, and hydrochlorothiazide, 25 mg/L, from day 21 after surgery, when rats had hypertension and proteinuria, until the death of the vehicle-treated rats. Molsidomine normalized systemic hypertension, only partially reduced proteinuria and serum creatinine levels, but significantly prolonged animal survival, particularly in the early stage of the disease. Lisinopril at a similar systemic blood pressure was even better than molsidomine in limiting proteinuria, preserving renal function, and prolonging survival, but triple therapy, despite being effective on blood pressure, offered no renoprotection or prolonged survival. Endothelin-1 (ET-1) levels, formed in excessive amounts by the kidneys of these animals, were reduced by molsidomine and lisinopril, but not by triple therapy. The prolongation of survival by NO donor could be attributed to its effect of reducing ET levels, which in turn may limit the smooth muscle cell proliferation and matrix accumulation responsible for organ and, especially, myocardial fibrosis in uremia.

SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction ENDOTHELIN IS A KEY MODULATOR OF PROGRESSIVE RENAL INJURY: EXPERIMENTAL DATA AND NOVEL THERAPEUTIC STRATEGIES

1. Glomerulosclerosis and tubulointerstitial damage are common histological abnormalities of many renal diseases that progress to end‐stage renal failure.