Reversal of Glomerulosclerosis after High-Dose Enalapril Treatment in Subtotally Nephrectomized Rats

Abstract

Interventions to block the renin-angiotensin system (RAS) halt the progression of renal lesions in renal damage models. It has recently also been reported that established glomerulosclerosis can be reversed by pharmacologic blockade of the RAS. It was the aim of this study to confirm that high doses of angiotensin-converting enzyme (ACE) inhibitors reverse established glomerulosclerosis and to extend the findings by providing quantitative information on glomerular geometry, podocytes and other glomerular cells, renal vessels and tubulointerstitial tissue. Male Sprague Dawley rats were subjected to subtotal surgical renal ablation (SNX) (n = 27) or sham operation (n = 31) and fed using a pair-feeding protocol. Eight weeks after surgery, rats were either sacrificed or allocated to two arms: enalapril treatment (48 mg/kg body wt per day administered in the drinking fluid for 4 wk) or no treatment. Renal morphology was evaluated after 8 or 12 wk, respectively, by stereology in tissue fixed by pressure-controlled perfusion. Both systolic BP and albumin excretion rate were significantly higher in SNX compared with sham-operated controls. They were significantly reduced in SNX after delayed enalapril treatment. The glomerulosclerosis (GSI), tubulointerstitial (TII), and vascular (VI) damage indices were significantly higher in all SNX groups than in sham-operated controls. At the end of the experiment (12 wk after SNX) GSI, TII, and VI were significantly lower in SNX with delayed enalapril treatment (0.77 +/- 0.18, 0.63 +/- 0.19 and 0.43 +/- 0.16, respectively) compared with untreated SNX (1.64 +/- 0.14, 1.16 +/- 0.34 and 0.67 +/- 0.29, respectively). GSI, TII, and VI were also significantly lower in SNX with delayed enalapril treatment compared with SNX sacrificed without treatment 8 wk after SNX. The same was true for glomerular volume. The number of podocytes was not affected by SNX, but podocyte volume was increased. Both indices remained unaffected by treatment. The numbers of cells within the mesangium and endothelial cells per glomerulus were significantly lower in SNX after delayed enalapril treatment compared with untreated SNX. These results strongly suggest regression of preexisting lesions, i.e., glomerular, tubular, and vascular remodeling as well as reversal of glomerular hypertrophy by ACE inhibitor treatment. The study confirms that high-dose ACE inhibitor treatment causes partial reversal of glomerular as well as interstitial lesions in subtotally nephrectomized rats.

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

“…The total area of the glomerular tuft (A T) was then determined as follows: AT ϭ AAT ϫ Acortex (where Acortex is total cortex area). The number of glomeruli per volume and per kidney, as well as mean glomerular volume, was calculated as described elsewhere (1).…”

Increased Capillary Branching Contributes to Angiotensin Type 1 Receptor Blocker (ARB)–Induced Regression of Sclerosis

“…4,8 -11,17-19 Studies by Adamczak et al 9 have shown that delayed intervention with high-dose enalapril in the 5/6 nephrectomy cautery model had parallel effects on glomerulosclerosis, tubulointerstitial, and vascular damage, with regression of existing lesions. Some previous studies have focused on a decreased area of sclerosis and decreased matrix accumulation as key mechanisms affecting regression.…”

“…We speculate that limitations of the podocyte may thus ultimately limit the potential of regression of glomerulosclerosis, unless specific therapies are identified that can specifically target increased regeneration of podocytes. Endothelial cells per glomerulus were decreased when regression was achieved in the studies by Adamczak et al 9 In additional studies by this group, the stereologic and topologic characteristics of glomerular capillary segments were assessed using standard morphometry techniques. Regression was associated with a decrease in mean glomerular volume, a decreased number of capillary segments per glomerulus, and a decreased total length of capillaries per glomerulus but without any significant change in the length of individual capillary segments and no change of numerical capillary density of the tuft.…”

“…Our 5/6 nephrectomy model has more severe hypertension and more severe progressive sclerosis induced by ligation of renal artery branches, in contrast to removal of renal mass by cautery. 9 In addition, we selected rats with similar biopsyproven regression and compared them with untreated remnant kidney rats with similar biopsy-proven progression; thus, these selected data are not necessarily representative of the more heterogeneous groups of all rats after 5/6 nephrectomy, where lesions may be much more variable.…”

Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

“…25 These observations suggest that during the development of TxG, primary damage to the GECs causes secondary podocyte damage that ultimately leads to podocytopenia and FSGS, since podocytes are considered postmitotic cells that are unable to replicate. 26,27 The mechanism of how primary damage to the GECs could cause secondary podocyte damage is currently unknown. A possible mechanism could be disruption of cytokine signaling from GECs to podocytes.…”