Regression of Glomerulosclerosis with High-Dose Angiotensin Inhibition Is Linked to Decreased Plasminogen Activator Inhibitor-1

Abstract

The potential and possible mechanisms for regression of existing glomerulosclerosis by angiotensin II type 1 receptor antagonist (AT1RA) and/or angiotensin I converting enzyme inhibitor (ACEI) were investigated. Adult male Sprague Dawley rats underwent 5/6 nephrectomy (Nx). Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into groups with equal biopsy sclerosis and treated for the next 4 wk until they were killed at 12 wk as follows: Control with no further treatment (CONT), high-dose AT1RA, high-dose ACEI, and varying AT1RA؉ACEI combinations. Hypertension and proteinuria induced by 5/6 Nx were significantly decreased by all treatments, except high-dose ACEI, which showed persistent proteinuria. High-dose AT1RA and ACEI markedly decreased progression of sclerosis, with ؊2.3% average decrease in sclerosis from biopsy to autopsy in AT1RA versus 194% increase in CONT (P < 0.0001). Glomerulosclerosis regressed, with less severe lesions at the time when the rats were killed than at biopsy in 62% of AT1RA-treated and 57% of ACEI-treated rats. In contrast, only 17 to 33% of rats in combination groups had regression. Alternatively, these data might be viewed as reflecting halting of progression, as some groups had higher BP and proteinuria. However, this potential confounding effect does not negate the effects to achieve regression of sclerosis in these rats. Regression was not explained by changes in mRNA of TGF-␤1 and matrix metalloproteinase-2 and -9 but was linked to decreased tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1. It is concluded that angiotensin inhibition mediates regression in part by effects on matrix modulation.

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

“…This model induces mild proteinuria, hypertension, and sclerosis by 4 weeks, with well-established sclerosis and worsened hypertension and sclerosis by week 8 and ongoing progressive sclerosis and death from uremia occurring in untreated 5/6 nephrectomy rats beyond 12 weeks. 4 Serum creatinine levels are increased at the time of 5/6 nephrectomy due to removal of the renal mass, with a progressive decrease in glomerular filtration rate as CKD worsens. 4 Rats were housed under conditions of a 12-hour light/dark cycle at 70°F with 40% humidity and 12 air exchanges per hour and received normal rat chow and water ad libitum (5001 diet, Purina Laboratory Rodent diet, 23.4% protein, 4.5% fat, 6.0% fiber, 0.4% sodium).…”

“…4 Serum creatinine levels are increased at the time of 5/6 nephrectomy due to removal of the renal mass, with a progressive decrease in glomerular filtration rate as CKD worsens. 4 Rats were housed under conditions of a 12-hour light/dark cycle at 70°F with 40% humidity and 12 air exchanges per hour and received normal rat chow and water ad libitum (5001 diet, Purina Laboratory Rodent diet, 23.4% protein, 4.5% fat, 6.0% fiber, 0.4% sodium). At 8 weeks, sclerosis was established by open renal biopsy, yielding on average 25 glomeruli, as previously reported.…”

“…At 8 weeks, sclerosis was established by open renal biopsy, yielding on average 25 glomeruli, as previously reported. 4 Rats were then divided into groups with an equal starting point of sclerosis in these biopsy specimens as previously reported. A subset of rats was then treated from week 8 to 12 with ARB (losartan, 80 mg/L drinking water; equivalent to 10 mg/kg body weight; and fourfold usual antihypertensive dose) and compared with untreated 5/6 nephrectomy rats, with matched biopsy levels of sclerosis.…”

“…10,12 Our previous data have shown that such ARBinduced improvement in sclerosis was indeed linked to less matrix accumulation in glomeruli, with an associated decrease in plasminogen activator inhibitor-1 (PAI-1) and increased plasmin activity. 4 PAI-1 is the major inhibitor of the plasmin/plasminogen activator system and inhibits both fibrinolysis and proteolysis. 11 PAI-1 also has plasmin-independent effects on matrix and cell migration.…”

“…13 Our previous data focused on modulation of matrix accumulation as a mechanism that contributes to regression of sclerosis. 4 Clearly, additional benefit could be achieved by not only reducing matrix but also augmenting capillary growth in remaining nonsclerosed segments of glomeruli. Interestingly, previous studies by Adamczak et al 10 observed fewer capillaries per glomerulus in a model of regression induced by ACEI.…”