Hao Ly

Increased glomerular capillary pressure alters glomerular cytokine expression.

Increased glomerular capillary hydrostatic pressure (PGC) is an important hemodynamic determinant of glomerular injury, but the molecular events responsible for this association are poorly understood. PGC is normal in spontaneously hypertensive rats (SHR), but uninephrectomy leads to an increase in PGC and accelerated glomerulosclerosis. Since recent studies have implicated transforming growth factor-beta 1 (TGF-beta 1) and platelet-derived growth factor sought to determine if uninephrectomy increased mRNA levels for TGF-beta 1 and PDGF in glomeruli of SHR. Since treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril lowers PGC and prevents glomerulosclerosis in uninephrectomized SHR, we also sought to determine if ACE inhibitor lowered mRNA levels for TGF-beta 1 and PDGF in the glomeruli of uninephrectomized SHR. PGC increased from 53 +/- 1 to 64 +/- 1 mm Hg 1 week after uninephrectomy in SHR (P < .05). The increase in PGC was associated with a sixfold rise in mRNA levels for TGF-beta 1 and a twofold rise in mRNA levels for PDGF in glomeruli. mRNA levels for PDGF returned to normal 2 weeks after nephrectomy, but the increase in mRNA levels for TGF-beta 1 was sustained. An increase in TGF-beta 1 immunostaining was detectable in glomeruli 4 weeks after nephrectomy. Treatment with ACE inhibitor normalized PGC (51 +/- 1 mm Hg) and prevented the rise in glomerular mRNA levels for TGF-beta 1 and PDGF. We conclude that an acute increase in PGC leads to increased TGF-beta 1 and PDGF expression in the glomerulus, thus linking changes in PGC to cytokine gene expression.

Attenuation of cyclosporine-induced hypertension by dietary fatty acids in the borderline hypertensive rat

The effects of dietary (10% calories) safflower (SAF), evening primrose (EPO), and fish oil (F) as sources of linoleic acid (control), gamma-linolenic acid, and long-chain n-3 fatty acids, respectively, on cardiovascular and renal responses to chronic (5 weeks) cyclosporine administration were studied in male borderline hypertensive rats. In one experiment (n = 9/group), oral administration of CsA at 0.1 mg/kg.day significantly increased awake systolic blood pressure vs. placebo in SAF-fed rats (P less than 0.01). This increase was prevented by both EPO (P less than 0.001) and F (P less than 0.01), in the absence of group differences in body weight gain or plasma electrolyte levels. In a second experiment, CsA also increased blood pressure vs. placebo in SAF-fed rats (P less than 0.001). While this increase was prevented by EPO (P less than 0.001), F had no significant effect. Differences in group blood pressure responses were not explained by group differences in body weight gain or trough levels of blood CsA. Renal function, assessed in anesthetized rats after week 5, demonstrated a CsA-related (10 mg/kg.day) decrease in whole-kidney GFR in SAF-fed animals vs. placebo (P less than 0.05) that was prevented by EPO and attenuated by F. EPO and F also tended to reduce the CsA-induced elevation in renovascular resistance, but this difference did not reach statistical significance. These findings suggest the potential of dietary EPO and F to offset nephrotoxic effects of CsA administration, and suggest that EPO may also be useful in countering CsA-induced hypertension.