M Mozes

Several lines of evidence suggest that local production of transforming growth factor-beta (TGF-beta) contributes to renal disease, particularly to the accumulation of the extracellular matrix protein that characterizes glomerulosclerosis and interstitial fibrosis. We have examined whether elevated levels of circulating TGF-beta adversely affect the kidney. We have studied mice that are transgenic for an active form of TGF-beta 1 under the control of murine albumin promoter and enhancer DNA sequences. These mice express the transgene exclusively in the liver and have elevated plasma concentrations of TGF-beta 1. Renal disease was seen in two of three lines of Alb/TGF-beta 1 transgenic mice; these two lines had the highest levels of hepatic transgene expression and the highest plasma TGF-beta 1 levels. Histologic abnormalities, which included mesangial expansion and thickened capillary loops, were noted in the glomeruli by 3 weeks of age. Interstitial fibrosis and tubular atrophy appeared subsequently. Mice from Line 25, the line with highest levels of TGF-beta 1, developed proteinuria by 5 weeks of age. These mice subsequently manifested nephrotic syndrome with ascites and progressive azotemia; uremic death occurred in more than 25% of the mice by 15 weeks of age. The glomeruli contained immune deposits in subendothelial and mesangial locations, but complement deposition was infrequent. Ultrastructural examination revealed an increase in extracellular matrix material, including collagen fibrils, in subendothelial and mesangial locations. Increased levels of circulating TGF-beta 1 induced progressive renal disease that was characterized by mesangial expansion, accumulation of glomerular immune deposits and matrix proteins, and interstitial fibrosis in this transgenic mouse model. These data suggest that chronically elevated circulating levels of TGF-beta 1 induce progressive glomerulosclerosis.

Transgenic mice (T26) bearing the envelope, regulatory, and accessory genes of HIV- I develop renal disease resembling human HIV-associated nephropathy (HIVAN). Effects of vehicle (VEH) and the angiotensin-converting enzyme inhibitor captopril (CAP) were examined in wild-type (WT) or T26 mice treated from 7 to 100 d of age. Mortality was lower in CAP T26 mice (30 mg/kg: 8%; 100 mg/kg: 12%) than VEH T26 mice (52%). The urinary protein/creatinine ratio was increased in VEH T26 mice (19.5+/-7.60) versus WT mice (6.1+/-0.83), but not in low-dose (7.3+/-0.94) or high-dose (8.2+/-1.02) CAP T26 mice. Blood urea nitrogen was higher in VEH T26 mice (52+/-16.2 mg/dl) than VEH WT mice (24+/-0.8). Blood urea nitrogen was also elevated in CAP WT (high dose: 43+/-2.1 mg/dl) and T26 mice (high dose: 42+/-2.4 mg/dl). Glomerular injury was higher in VEH T26 mice (6.8+/-0.58) than VEH WT mice (0.2+/-0.08) or CAP T26 mice (low dose: 1.1+/-0.17; high dose: 0.7+/-0.13). Tubulointerstitial injury was also greater in VEH T26 mice (1.1+/-0.10) than VEH WT mice (0.2+/-0.08) or CAP T26 mice (low dose: 0.4+/-0.10; high dose: 0.3+/-0.10). These data validate recent nonrandomized studies of captopril in HIV-infected patients, and suggest that an angiotensin-converting enzyme substrate is an important mediator in HIVAN. A randomized placebo-controlled trial of captopril in HIVAN may be warranted.

Increasing number of evidence suggest that gastric mucosal protection can be induced also centrally. Several neuropeptides, such as TRH, amylin, adrenomedullin, enkephalin, beta-endorphin, nociceptin, nocistatin, ghrelin or orexin given centrally induce gastroprotection and the dorsal vagal complex and vagal nerve may play prominent role in this centrally initiated effect. Since also cannabinoid receptors are present in the dorsal vagal complex, we aimed to study whether activation of central cannabinoid receptors result in gastric mucosal defense and whether there is an interaction between cannabinoids and endogenous opioids. Gastric mucosal damage was induced by 100% ethanol in rats. The cannabinoids were given intravenously (i.v.) or intracerebroventricularly (i.c.v.), while the antagonists were given i.c.v or intracisternally (i.c.). Gastric lesions were evaluated macroscopically 60 min later. Anandamide, methanandamide and WIN55,212-2 reduced ethanol-induced mucosal lesions after both peripheral (0.28-5.6 micromol/kg, 0.7-5.6 micromol/kg and 0.05-0.2 mumol/kg i.v., respectively) and central (2.9-115 nmol/rat, 0.27-70 nmol/rat and 1.9-38 nmol/rat i.c.v., respectively) administration. The gastroprotective effect of anandamide and methanandamide given i.c.v. or i.v.was reversed by the CB(1) receptor antagonist SR141716A (2.16 nmol i.c.v.). Naloxone (27.5 nmol i.c.v.) also antagonized the effect of i.c.v. or i.v. injected anandamide and WIN55,212-2, but less affected that of methanandamide. The gastroprotective effect of anandamide was diminished also by endomorphin-2 antiserum. In conclusion it was first demonstrated that activation of central CB(1) receptors results in gastroprotective effect. The effect is mediated at least partly by endogenous opioids.