Mechanisms of the Puromycin-Induced Defects in the Transglomerular Passage of Water and Macromolecules

Bohrer, M. P.; Baylis, Christine; Robertson, Channing R.; Brenner, Barry M.; Troy, Julia L.; Willis, Wayne T.

doi:10.1172/jci108751

Cited by 140 publications

(55 citation statements)

References 37 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increased fractional clearances of anionic dextran sulfates in PA nephrosis without increased clearances of neutral dextrans of the same sizes is also consistent with a loss of capillary wall charge in this model (24). Histochemical and ultrastructural studies demonstrate the major site of negative charge to be or!…”

Section: Resultssupporting

confidence: 73%

“…This distribution of early epimembranous complex deposits corresponds to the localization of polyanionic glomerular sialoprotein on epithelial cells and in filtration slits (17)(18)(19). Recent physiologic and ultrastructural tracer studies have suggested a role for this negatively charged material in regulating the permeability of the glomerular capillary wall to circulating macromolecules in both normal and disease states (20)(21)(22)(23)(24). However, the effect of alterations in intrinsic properties of the glomerulus on the localization of immune complexes has not been previously investigated.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Effect of aminonucleoside nephrosis on immune complex localization in autologous immune complex nephropathy in rats.

Couser¹,

Jermanovich²,

Belok³

et al. 1978

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T The effect of increased capillary perilmealility on1 glomerular immultine comiiplex localizationi was studied in rats immiluniized with proximial tul)ular anitigeni (Fx1A) to induce autologouis imnmunie complex nephropathy (AICN). AICN rats were made proteinuric 1)V-injection or uniilateral renal perfusion with amiiinoinucleoside of puromycin (PA) before developing sul)epithelial conmplex deposits. Control AICN kidneys developed diffuse granular deposits of IgG and Fx1A oIn the subepithelial surf'ace of the glomerular b)asement membrane (GBM) at 3 wk by immuiinofluiorescence and electron microscopy, and dep(isits increased in sul)-se(quienit weekly biopsies. In conitrast, PA-nephrotic AICN kidneys developed few or no GBM deposits and a significant increase in mesangial localization of IgG and FxlA during the period of PA-induced proteinuria. These alterationis in complex localizationi were documenited 1)oth in rats with PA nephrosis andl in unilaterally PA-inephrotic kidneys compared with conitralateral controls in the sanme animiials, thus excluidinig any effect of PA on the imnililiiopatlhogenetic mlechaniisnm in AICN as ani explaniation for these finidings. The absence of GBMi deposits closely correlated with reducedl stainiing for polyanionic glomierilar sialoproteini in proteinutiric kidneys, siniee PA-perfuised kidneys studied 2 wk after resdoltutioin of proteinutria demiion strated retuirni of niormlial staininig for sialoprotein Portionis of this work were presented at the 8th Ainutal

show abstract

Section: Resultssupporting

confidence: 73%

mentioning

confidence: 99%

Effect of aminonucleoside nephrosis on immune complex localization in autologous immune complex nephropathy in rats.

Couser¹,

Jermanovich²,

Belok³

et al. 1978

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…The pattern of glomerular sieving curve alteration found in humans (9) and by our present study in the rat appears unique of enalapril treatment. We found that 0 of small (radius < 30 A) and large test macromolecules (radius > 50 A) were significantly reduced while in the majority of other studies, performed in animals (23,36,37) and in humans (27,38,39), restoration of glomerular selective function was invariably associated with a reduction in 0 of largest dextran molecules, as in the present study, but with a concomitant increase in 0 of small dextran molecules.…”

Section: Discussionsupporting

confidence: 73%

Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat.

Remuzzi¹,

Puntorieri²,

Battaglia³

et al. 1990

J. Clin. Invest.

237

132

View full text Add to dashboard Cite

The effect of enalapril on glomerular hemodynamics and permselectivity and on subsequent sclerosis was studied in male MWF/Ztm rats which spontaneously develop proteinuria and glomerular structural damage. Untreated group 1 and enalapril-treated group 2 (50 mg/liter, in the drinking water) underwent micropuncture studies after 2 mo of observation. After the same period of treatment, group 3 (untreated) and group 4 (enalapril treated) were used for determination of whole-kidney function and neutral dextran clearances. Group 5 (untreated) and group 6 (enalapril treated) were followed for an additional 4 mo and used for kidney function and morphological studies. Enalapril significantly lowered systolic blood pressure, which was elevated in untreated groups, and significantly reduced proteinuria (295±64 vs. 128±24 mg/24 h by the end of the study). Despite the reduced renal perfusion pressure, whole-kidney glomerular filtration rate was higher in enalapril-treated than in untreated rats (0.96±0.14 vs. 0.81±0.10 ml/min, P < 0.05) as was the single nephron glomerular filtration rate (54±7.1 vs. 46±4.0 nl/min, P < 0.05). The single glomerular afferent plasma flow was comparable in both groups. Enalapril reduced mean glomerular capillary hydraulic pressure from the normal value of 51±1 mmHg (untreated rats) to a value lower than normal (44±1 mmHg, P < 0.001). These hemodynamic changes were associated with a significant reduction in afferent (r23%) and efferent (zv 26%) arteriolar resistance. The mean ultrafiltration coefficient was two times higher in the enalapril (0.126±0.027 nl/s per mmHg) than in the untreated group (0.061±0.023 nl/s per mmHg). The clearance of dextran macromolecules relative to that of inulin was significantly reduced for all molecular sizes studied (26-64 A) in enalapril-treated vs. untreated rats. Theoretical analysis of dextran fractional clearances using a heteroporous model of neutral solute transport across the glomerular capillary wall indicated that enalapril affected glomerular membrane size selective properties, reducing uniformly the radius of hypothetical membrane pores. Enalapril treatment also significantly limited (P < 0.01) the development of glomerular structural lesions (mean percentage of sclerotic glomeruli was 4.2±3.5% [treated] vs. 28±15% luntreated] rats at the end of the study) as well as tubulo-interstitial damage. These results suggest that the protective effect of enalapril on the develop-

show abstract

“…Other investigators have reported similar changes in rats following acute and chronic administration of AMN (1,18). Persistent injury to glomerular epithelium is believed to result in proteinuria due to a diminution in the electrostatic barrier function of the glomerular capillary wall (2,20). An increase in glomerular capillary permeability has been shown to result not only in proteinuria, but also in an increased uptake and decreased clearance of proteins from the mesangium (15,16).…”

Section: Discussionmentioning

confidence: 76%

“…Unilateral renal perfusion with saline did not alter renal function or protein excretion (4). Other investigators have observed a decrease in GFR and renal blood flow in both kidneys of rats following acute parenteral administration of AMN (2).…”

Section: Discussionmentioning

confidence: 80%

Experimental Focal Segmental Glomerulosclerosis: Correlation with Protein Excretion, Glomerular Filtration Rate, and Renal Plasma Flow

et al. 1984

View full text Add to dashboard Cite

ABSTRACT. A rat model of focal segmental glomerulosclerosis (FSGS) produced by repeated injections of aminonucleoside (AMN) of puromycin was used to evaluate the relative roles of hemodynamic alterations and AMN-induced glomerular visceral epithelial cell injury in the development of FSGS.Twenty rats received three intraperitoneal injections of AMN on days 1, 21, and 28 and developed significant proteinuria. On day 50, 14 rats (group 1) underwent selective left renal perfusion with AMN and six rats (group 2) received left renal perfusion with saline. At sacrifice on day 70 or 110, group 2 rats had similar values in left and right kidneys for glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and the amount of FSGS (13.1 f 5.6% in left and 12.9 2 7.8% in right). In contrast, group 1 rats manifested a significantly higher amount of FSGS in right kidneys as compared to left kidneys (3.1 f 1.3% in left and 6.3 f 2.0% in right, as well as significantly diminished GFR and ERPF in left as compared to right kidneys. A higher degree of FSGS was seen in kidneys with a higher GFR and ERPF. A positive correlation was observed between the mean 24-h protein excretion of the rats and the percentage of FSGS in left and right kidneys ( r = 0.66, p < 0.01). (Pediatr Res 18:1195-1201, 1984 Abbreviations FSGS, focal segmental glomerulosclerosis AMN, aminonucleoside ERPF, effective renal plasma flow GFR, glomerular filtration rate Idiopathic nephrotic syndrome associated with FSGS is characterized by resistance to steroid therapy, frequent progression to end stage renal disease, and recurrence in the transplanted kidney (5). The etiological factors and the pathogenic mechanisms for the development of proteinuria as well as the lesion of FSGS are not fully understood.Several studies have pointed to the contribution of hemodynamic changes and increased filtration of proteins in the genesis Received February 8, 1983; accepted May 10, 1984 chronic proteinuria and progressive FSGS in rats by repeated injections of the aminonucleoside of puromycin. These authors proposed that irreversible glomerular epithelial injury from a direct toxic effect of AMN was the primary event leading to proteinuria and development of FSGS. They observed a higher incidence of FSGS in rats who received AMN following unilateral nephrectomy (7,20). The increase in FSGS following uninephrectomy could have been a result of 1) a higher dose of AMN reaching the single kidney and leading to greater epithelial cell injury or 2) the effects of increased blood flow and increased glomerular capillary pressure in the solitary kidney as suggested in several earlier studies (3,8, 11,19). The present study was designed to examine the relative roles of direct epithelial cell injury and alterations in renal plasma flow and GFR in the pathogenesis of FSGS produced by repeated administration of AMN in rats. MATERIALS AND METHODSThe experimental design is outlined in Figure 1. Twenty male Sprague-Dawley rats weighing 75-100 gm were divided into two groups. An in...

show abstract

Mechanisms of the Puromycin-Induced Defects in the Transglomerular Passage of Water and Macromolecules

Cited by 140 publications

References 37 publications

Effect of aminonucleoside nephrosis on immune complex localization in autologous immune complex nephropathy in rats.

Effect of aminonucleoside nephrosis on immune complex localization in autologous immune complex nephropathy in rats.

Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat.

Experimental Focal Segmental Glomerulosclerosis: Correlation with Protein Excretion, Glomerular Filtration Rate, and Renal Plasma Flow

Contact Info

Product

Resources

About