Albuminuria causes lysozymuria in rats with Heymann nephritis

Albuminuria causes lysozymuria in rats with Heymann nephritis. To determine if changes in dietary protein intake alter renal excretion of small molecular weight proteins in passive Heymann nephritis, 21 rats with passive Heymann nephritis were fed 8.5% protein for 12 days after injection with antiserum. Dietary protein intake was then increased to 40% in 10 rats (LP-HP) while 11 rats remained on 8.5% protein (LP-LP). Lysozymuria (UlysV) increased from 66.5 ±31.0 meg/day to 457.5 ± 98.0 mcg/day (P < 0.001) after five days in LP-HP, but was unchanged in LP-LP. Albuminuria (UalbV) increased only in LP-HP, from 168 ± 23 mg/day to 447 ± 45 mg/day (P < 0.001). Urinary lysozyme excretion correlated with UalbV (r = 0.737, P < 0.001), and changes in UlysV correlated with changes in UalbV (r = 0.657, P < 0.01). To determine whether the increase in UlysV was the direct effect of the change in diet, enalapril 40 mg/kg/day was administered to prevent the increase in UalbV that occurs when these rats are fed a high protein diet. Twelve rats were fed 8.5% (LP) and 10 were fed 40% protein (HP) from the time of injection with antiserum. Six LP (LPE) and five HP (HPE) received enalapril. UlysV was 873 ± 391 meg/day in HP and nearly undetectable in the other three groups. UalbV was significantly greater in HP (368 ± 60 mg/day) compared to the other three groups (114 ± 16 in LP, 136 ± 44 in HPE, 95 ± 21 in LPE). A third group of nephrotic rats, maintained on a constant diet of 21% protein had enalapril added to their drinking water. UiysV decreased from 49 ± 9 meg/day to less than 2 meg/day (P < 0.001) and UalbV decreased from 516 ± 67 to 183 ± 32 mg/day (P < 0.001). Both UlysV and UalbV remained unchanged in untreated rats. Lysozyme, an enzyme normally entirely reabsorbed by the kidney, is found in the urine of rats with passive Heymann nephritis, and increases when dietary protein intake is increased. High protein diets increase UlysV only in as much as UalbV is increased, and when UalbV is reduced by use of an angiotensin converting enzyme inhibitor in the presence of a high protein diet UlysV is reduced in a parallel fashion, suggesting that albuminuria itself decreases the capacity of the renal tubule to reabsorb lysozyme

GFR increases before renal mass or ODC activity increase in rats fed high protein diets

GFR increases before renal mass or ODC activity increase in rats fed high protein diets. Consumption of a high protein diet causes renal hypertrophy and increased glomerular filtration rate (GFR). To determine the relationship between increases in GFR, renal ornithine decarboxylase activity (ODC), arginase activity, and renal growth, dietary protein intake was increased from 8.5% to 40% in 50 male Sprague-Dawley rats (HP). Forty-one rats remained on 8.5% protein as time controls (LP). Eight to 17 animals were killed daily for measurement of kidney weight (kidney wt), ODC and arginase activities, total kidney protein and DNA content. GFR increased within the first 24 hours after the increase in dietary protein and reached a maximum within 48hrs. ODC increased from 9.7 ± 0.8 U/g to a peak of 170 ± 35 U/g at 48 hours, decreasing to a stable value of 28.6 ± 8.0 U/g at 72 hours and 25.4 ± 5.1 U/g at 168 hours, a value significantly greater than that at time zero. Arginase activity did not change. Kidney wt as percent body weight (body wt) increased after the initial increase in both GFR and in ODC activity. The peak in ODC activity corresponded with the maximum increase in GFR and preceded the increase in renal mass. After GFR stabilized, ODC activity decreased to a plateau and renal growth relative to body wt ceased. The increase in kidney weight was accompanied by a parallel increase in total kidney protein. Kidney protein/ kidney DNA ratio increased significantly by 96 hours, indicating that renal hypertrophy had occurred. The sequence of these events suggests that increasing GFR may trigger the rise in ODC activity

Selective Cyclooxygenase-2 Inhibitor Suppresses Renal Thromboxane Production but Not Proliferative Lesions in the MRL/lpr Murine Model of Lupus Nephritis

BACKGROUND: Proliferative lupus nephritis (LN) is marked by increased renal thromboxane (TXA(2)) production. Targeting the TXA(2) receptor or TXA(2) synthase effectively improves renal function in humans with LN and improves glomerular pathology in murine LN. This study was designed to address the following hypotheses: 1) TXA(2) production in the MRL/MpJ-Tnfrsf6(lpr)/J (MRL/lpr) model of proliferative lupus nephritis is COX2-dependent, and 2) COX2 inhibitor therapy improves glomerular filtration rate (GFR), proteinuria, markers of innate immune response, and glomerular pathology. METHODS: 20 female MRL/lpr and 20 BALB/cJ mice were divided into two equal treatment groups: 1) SC-236, a moderately selective COX2 inhibitor, or 2) vehicle. After treatment from 10 to 20 weeks of age, the effectiveness of inhibition of TXA(2) was determined by measuring urine TXB(2). Response endpoints measured at 20 weeks of age were renal function (GFR), proteinuria, urine nitrate + nitrite (NO(X)), and glomerular histopathology. RESULTS: SC236 therapy reduced surrogate markers of renal TXA(2) production during early, active glomerulonephritis. When this pharmacodynamic endpoint was reached, therapy improved GFR. Parallel reductions in markers of the innate immune response (urine NO(X)) during therapy were observed. However, the beneficial effect of SC236 therapy on GFR was only transient, and renal histopathology was not improved in late disease. CONCLUSIONS: These data demonstrate that renal TXA(2) production is COX2-dependent in murine LN and suggest that NO production is directly or indirectly COX2-dependent. However, COX2 inhibitor therapy in this model failed to improve renal pathology, making COX2 inhibition a less attractive approach for treating LN