Kerri Thai

ASSOCIATION OF ANGIOTENSINOGEN GENE T235 VARIANT WITH PROGRESSION OF IMMUNOGLOBIN A NEPHROPATHY IN CAUCASIAN PATIENTS

Genetic variability in the renin-angiotensin system may modify renal responses to injury and disease progression. We examined whether the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, and the A1166--> C polymorphism of the angiotensin II type 1 receptor gene may be associated with disease progression in 168 Caucasian patients with IgA nephropathy. All patients had serial measurements of their creatinine clearance, proteinuria, and blood pressure (mean+/-SD) with a follow-up of 6.1+/-4.7 yr. The genotype frequencies for each gene were consistent with Hardy-Weinberg equilibrium, and were similar to those of 100 Caucasian control subjects. We examined two primary outcomes: (a) the rate of deterioration of Ccr, and (b) the maximal level of proteinuria. We found that patients with the AGT MT (n = 79) and TT (n = 29) genotypes had a faster rate of deterioration of Ccr than those with the MM (n = 60) genotype (i.e., median values, -6.6 and -6.2 vs. -3. 0 ml/min/yr, respectively; P = 0.01 by Kruskal-Wallis test). Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype (i.e., median values, 2.5 and 3.5 vs. 2.0 g/d, respectively; P < 0.02 by Kruskal-Wallis test). Neither the ACE insertion/deletion nor angiotensin II type I A1166--> C gene polymorphism was associated with disease progression or proteinuria in univariate analysis. Multivariant analysis, however, detected an interaction between the AGT and ACE gene polymorphisms with the presence of ACE/DD polymorphism adversely affecting disease progression only in patients with the AGT/MM genotype (P = 0.008). Neither of these gene polymorphisms was associated with systemic hypertension. Our results suggest that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy.

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.