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SUMMARY:Diabetic nephropathy (DN) is characterized by an early, progressive expansion and sclerosis of the glomerular mesangium leading to glomerulosclerosis. This is associated with parallel fibrosis of the renal interstitium. In experimental renal scarring, the protein cross-linking enzyme, tissue transglutaminase (tTg), is up-regulated and externalized causing an increase in its crosslink product, ⑀-(␥-glutamyl)-lysine, in the extracellular space. This potentially contributes to the extracellular matrix (ECM) accumulation central to tissue fibrosis by increasing deposition and inhibiting breakdown. We investigated if a similar mechanism may contribute to the ECM expansion characteristic of DN using the rat streptozotocin model over 120 days. Whole kidney ⑀-(␥-glutamyl)-lysine (HPLC analysis) was significantly increased from Day 90 (ϩ337%) and peaked at Day 120 (ϩ650%) (p Ͻ 0.05). Immunofluorescence showed this increase to be predominantly extracellular in the peritubular interstitial space, but also in individual glomeruli. Total kidney transglutaminase (Tg) was not elevated. However, using a Tg in situ activity assay, increased Tg was detected in both the extracellular interstitial space and glomeruli by Day 60, with a maximal 53% increase at Day 120 (p Ͻ 0.05). Using a specific anti-tTg antibody, immunohistochemistry showed a similar increase in extracellular enzyme in the interstitium and glomeruli. To biochemically characterize glomerular changes, glomeruli were isolated by selective sieving. In line with whole kidney measurement, there was an increase in glomerular ⑀-(␥-glutamyl) lysine (ϩ361%); however, in the glomeruli this was associated with increases in Tg activity (ϩ228%) and tTg antigen by Western blotting (ϩ215%). Importantly, the ratio of glomerular ⑀-(␥-glutamyl) lysine to hydroxyproline increased by 2.2-fold. In DN, changes in the kidney result in increased translocation of tTg to the extracellular environment where high Ca 2ϩ and low GTP levels allow its activation. In the tubulointerstitium this is independent of increased tTg production, but dependent in the glomerulus. This leads to excessive ECM cross-linking, contributing to the renal fibrosis characteristic of progressive DN. (Lab Invest 2001, 81:705-716).

Intrarenal hemodynamics were estimated clinically in essential hypertension. Two-week studies were performed in 30 patients with essential hypertension who were given a regular sodium diet in the first week and a sodium-restricted diet in the second week. Intrarenal hemodynamic parameters such as afferent arteriolar (preglomerular) resistance, efferent arteriolar resistance, and glomerular hydrostatic pressure were calculated from renal clearances and plasma total protein concentration measured on the last day of the regular sodium diet. Calculations were based on Gomez's equations with the assumption that the gross filtration coefficient of glomerular capillaries was normal. The increase in afferent arteriolar resistance (8,100 +/- 500 dyne.sec.cm-5) was significantly correlated with an elevation in mean arterial pressure (120 +/- 2 mm Hg), whereas glomerular pressure (56 +/- 1 mm Hg) and efferent arteriolar resistance (2,500 +/- 100 dyne.sec.cm-5) remained normal. The renal function curve (pressure-natriuresis relation) was drawn by plotting urinary sodium excretion on the y axis as a function of mean arterial pressure on the x axis, both of which were measured on the last 3 days of each week. The extrapolated x intercept (107 +/- 2 mm Hg) of the renal function curve was strongly correlated in a 1:1 fashion with the sum of the arterial pressure drop from the aorta to the renal glomeruli plus the opposing pressures against glomerular filtration at glomeruli (r = 0.7, p less than 0.001) on the regular sodium diet, suggesting that the difference between mean arterial pressure on the regular sodium diet and the extrapolated x intercept represented the effective filtration pressure across the glomerular capillaries on the regular sodium diet.(ABSTRACT TRUNCATED AT 250 WORDS)

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To examine the effect of age on a compensatory renal growth, adaptive renal hemodynamics and renal histology in solitary kidney, unilateral nephrectomy was performed in young rats at 4 weeks of age (group 4-UN) or in adult rats at 10 weeks of age (group 10-UN). Urinary protein was measured every 4 weeks until the 48th week. Serial changes in kidney weight, glomerular filtration rate (GFR), renal plasma flow (RPF) and renal histology were investigated at weeks 4, 8, 24 and 48 after the uninephrectomy. Increase in proteinuria was significantly greater in group 4-Un than in group 10-UN from weeks 32–48 after uninephrectomy. The remnant kidney showed a compensatory enlargement which was more marked in group 4-UN than in group 10-UN at weeks 24 and 48. GFR or RPF in group 4-UN was significantly greater than that in group 10-UN at weeks 4,8, and 24. Focal and segmental glomerular sclerosis was evident at week 24 or later in the uninephrectomized rats, being more severe in group 4-UN than in group 10-UN at week 48. We conclude that uninephrectomy in young rats leads to augmented compensatory renal growth and glomerular hyperperfusion, resulting in extensive glomerular sclerosis compared to that in adult rats.