ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease

Abstract

Today angiotensin II inhibition is primarily used to slow the rate of progression of kidney diseases. There is evidence that these therapies can induce a partial regression of glomerular lesions. However, we do not know yet the extent of sclerotic lesion regression and whether new glomerular tissue is formed to help support the renal function. We used male Munich Wistar Fromter (MWF) rats, an experimental model for progressive kidney disease, to quantify kidney structural lesions upon angiotensin-converting enzyme (ACE) inhibition therapy. Animals were studied at 50 weeks of age, when renal function and structure are severely altered, and after a 10-week observation period, without or with treatment with lisinopril (80 mg/l in drinking water). A group of untreated Wistar rats was used as controls. With age, proteinuria, and serum creatinine worsen, but lisinopril almost normalized proteinuria and stabilized serum creatinine. Serial section analysis of whole glomerular tufts showed that at baseline, glomerulosclerosis affected the entire glomerular population, and that these changes further increased with age. Lisinopril significantly reduced incidence and extent of glomerulosclerosis, with the presence of glomerular tufts not affected by sclerosis (23% of glomeruli). Glomerular volume was not significantly affected by treatment, and glomerular mass spared from sclerosis increased from 46.9 to 65.5% upon treatment, indicating consistent regeneration of glomerular tissue. Lisinopril normalized baseline glomerular transforming growth factor-beta and alpha-smooth muscle actin overexpression, and prevented worsening of interstitial changes. Hence, ACE inhibition, which is widely used in human kidney disease, may not only halt the progression of renal failure, but also actually induce the regeneration of new renal tissue.

Podocyte Repopulation Contributes to Regression of Glomerular Injury Induced by Ace Inhibition

“…[12][13][14] In the latter study, combined treatment with an ACE inhibitor and an AT1R blocker given from 25 to 40 weeks of age completely reversed proteinuria, and halted progressive glomerulosclerosis, particularly in glomeruli with mild sclerotic lesions. 13 Recently three-dimensional reconstruction of the capillary tuft by serial section analysis allowed us to document the effects of administration of a high dose of an ACE inhibitor starting at 50 weeks of age, when rats had a more advanced nephropathy.…”

“…Inhibition of collagen synthesis, 7 trans-forming growth factor-␤, 14 and plasminogen activator inhibitor-1 expression 10,11 were indeed proposed as possible mechanisms responsible for sclerosis regression. However, the possibility that ACE inhibitors or AT1R antagonists can modulate glomerular cell survival and repair is intriguing and not well explored yet.…”

Mechanisms and Treatment of CKD

“…[84][85][86] A long-term follow-up of the REIN study showed that the rate of measured GFR decline progressively improved to a level of about 1 ml/min per 1.73 m 2 per year after at least 5 years of continued ramipril use, which approximates the average age-related loss in GFR over time in healthy participants. 87 Moreover, a breakpoint was identified in the slope of GFR changes over time that started to increase after 36 months of treatment a finding that led to hypothesize that renal disease can regress.…”

“…87 Moreover, a breakpoint was identified in the slope of GFR changes over time that started to increase after 36 months of treatment a finding that led to hypothesize that renal disease can regress. 88 Using a technique for three-dimensional reconstruction of the glomerular capillary tuft, Andrea Remuzzi et al 84 showed in rats with advanced proteinuric nephropathy that administration of high-dose lisinopril reduced the volume of sclerosis in most glomeruli, unless they were almost totally sclerosed, and increased the volume of normal capillary tissue by up to 40%. Kidney repair has been definitely documented in seven proteinuric patients with idiopathic membranous nephropathy treated with the anti-CD20 mAb, rituximab; these patients, in parallel with complete remission of the nephrotic syndrome, showed reabsorption of characteristic subepithelial electron-dense immune deposits and reversion of foot process effacement and loss of intact slit diaphragms at repeat biopsy evaluation.…”

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

“…For example, in animal models, reduction of proteinuria induced by treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with increased number of podocytes and regression of glomerulosclerosis. 13 Indeed, although podocytes have limited capacity to divide, they can potentially get replaced by a population of renal progenitor cells (RPCs) localized within the Bowman capsule. [14][15][16][17] In this study, we hypothesized that proteinuria may interfere with the generation of novel podocytes via direct or indirect impairment of regenerative mechanisms.…”