Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

Abstract

Abstract-Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week-old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.

Role of mineralocorticoid receptor on atrial structural remodeling and inducibility of atrial fibrillation in hypertensive rats

“…We confirmed that the serum concentration of aldosterone did not increase in the DS+HS group compared with that of the DS+NS group. Recent basic studies have demonstrated that MR activation is important in the etiology of cardiovascular and renal diseases not only in highaldosterone status but also in low-aldosterone hypertension, 12,36 which are consistent with our results. How is MR activated in lowaldosterone hypertension?…”

Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism

“…Nagase et al [34] reported that eplerenone improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Iwakura et al showed that in 111 patients with bilateral hyperaldosteronism treated with mineralocorticoid receptor antagonists, urinary albumin excretion and eGFR were significantly decreased at 12 months after treatment; these results were consistent with the results from our study [35].…”

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

“…9,31 Further evidence suggests a role of oxidative stress in the pathogenesis of podocyte injury in Aldo-infused rats. 3 However, the source of Aldo-induced oxidative stress in podocytes is still poorly characterized.…”

“…In particular, Aldo causes podocyte injury in vivo and in vitro, and Aldo blockade is therapeutic in renal injury. 5,[7][8][9] However, the underlying mechanism for Aldoinduced injury in the kidney (in general) and in the podocytes (in particular) is not well understood.Podocytes are terminally differentiated, high-energy required cells that have lost mitotic activity, and typically do not proliferate after injury. 10 Mitochondria (mt) dysfunction (MtD) is involved in several diseases and progressive disease processes, including glomerulosclerosis, in which podocyte injury is a crucial event in sclerosis formation.…”

“…In particular, Aldo causes podocyte injury in vivo and in vitro, and Aldo blockade is therapeutic in renal injury. 5,[7][8][9] However, the underlying mechanism for Aldoinduced injury in the kidney (in general) and in the podocytes (in particular) is not well understood.…”