Renal impairment in deoxycorticosterone acetate‐salt hypertensive rats

Summary: This study has compared renal function in deoxycorticosterone (DOCA)‐salt hypertensive Wistar rats (uninephrectomy followed by administration of DOCA 25 mg subcutaneously every fourth day and 1% NaCl in the drinking water) with various control rats using the isolated perfused kidney preparation. The systolic blood pressure of DOCA‐salt hypertensive rats was 180 ± 10 mmHg (uninephrectomy controls: 136 ± 9 mmHg) while normalization of calcium intake (DOCA‐Ca rats, 1% CaCl₂ in water) attenuated this increase (systolic blood pressure, 146 ± 5 mmHg). Renal mass corrected for body weight increased by 25% after uninephrectomy, 55% in uninephrectomized rats given NaCl, 152% in DOCA‐salt rats and 147% in DOCA‐Ca rats. At a renal perfusion pressure of 135 mmHg, isolated perfused kidneys from DOCA‐salt rats showed decreases of 48% in glomerular filtration rate and 69% in sodium excretion with an increase of 44% in renal vascular resistance compared with uninephrectomized rats. There were no significant differences in renal function between DOCA‐salt and DOCA‐Ca rats. Histological assessment of renal pathology showed proximal tubular hypertrophy and hyperplasia, marked focal distal tubular atrophy, interstitial fibrosis and glomerular hypercellularity in DOCA rats compared with UNX rats. Lesions were less obvious in UNX‐salt or DOCA‐Ca rats. The lack of direct correlation between alterations in function and pathology may be explained by the compensatory effect of remaining healthy or hypertrophied nephrons. Thus, the DOCA‐salt model of hypertension in rats is associated with marked structural kidney damage and severely decreased kidney function. Marked attenuation of systemic hypertension by normalizing calcium intake in DOCA‐salt rats did not prevent impairment of kidney function.     

Recurrent aphthous ulceration with zinc deficiency and cellular immune deficiency.

Zinc deficiency (serum zinc level 65 micrograms/dl) and cellular immune deficiency (confirmed by lymphoblastic transformation assay) were found in a 15-year-old boy who had had recurrent aphthous ulceration for 6 years. Despite the previous therapy (orally administered steroid, isoprinosine, interferon, lysozyme, and local treatment), the ulcers recurred monthly. After 3 months of zinc therapy (50 mg zinc sulfate orally three times daily) the aphthae disappeared and did not reappear for 1 year. The lymphoblastic transformation activity and serum zinc levels were also normalized with this treatment.     

Interleukin-1beta stimulates human renal fibroblast proliferation and matrix protein production by means of a transforming growth factor-beta-dependent mechanism

One of the hallmarks of progressive renal disease is the development of tubulointerstitial fibrosis. This is frequently preceded by macrophage infiltration, raising the possibility that macrophages relay fibrogenic signals to resident tubulointerstitial cells. The aim of this study was to investigate the potentially fibrogenic role of interleukin-1beta (IL-1beta), a macrophage-derived inflammatory cytokine, on cortical fibroblasts (CFs). Primary cultures of human renal CFs were established and incubated for 24 hours in the presence or absence of IL-1beta. We found that IL-1beta significantly stimulated DNA synthesis (356.7% +/- 39% of control, P <.003), fibronectin secretion (261.8 +/- 11% of control, P <.005), collagen type 1 production, (release of procollagen type 1 C-terminal-peptide, 152.4% +/- 26% of control, P <.005), transforming growth factor-beta (TGF-beta) secretion (211% +/- 37% of control, P <.01), and nitric oxide (NO) production (342.8% +/- 69% of control, P <.002). TGF-beta (1 ng/mL) and the phorbol ester phorbol 12-myristate 13-acetate (PMA, 25 nmol/L) produced fibrogenic effects similar to those of IL-1beta. Neither a NO synthase inhibitor (N(G)-methyl-l-arginine, 1 mmol/L) nor a protein kinase C (PKC) inhibitor (bis-indolylmaleimide 1, 1 micromol/L) altered the enhanced level of fibronectin secretion or DNA synthesis seen in response to IL-1beta treatment. However, addition of a TGF-beta-neutralizing antibody significantly reduced IL-1beta-induced fibronectin secretion (IL-1beta + IgG, 262% +/- 72% vs IL-1beta + alphaTGF-beta 156% +/- 14%, P <.02), collagen type 1 production (IL-1beta + IgG, 176% +/- 28% vs IL-1beta + alphaTGF-beta, 120% +/- 14%, P <.005) and abrogated IL-1beta-induced DNA synthesis (245% +/- 49% vs 105% +/- 21%, P <.005). IL-1beta significantly stimulated CF DNA synthesis and production of fibronectin, collagen type 1, TGFbeta, and NO. The fibrogenic and proliferative action of IL-1beta on CF appears not to involve activation of PKC or production of NO but is at least partly TGFbeta-dependent.