Local renal aldosterone production induces inflammation and matrix formation in kidneys of diabetic rats

Abstract

Recently, we reported the presence of a local renal aldosterone production. In the present study, we tested the hypothesis that local aldosterone production in the kidney contributes to renal inflammation, matrix formation and albuminuria associated with diabetes. We evaluated changes in renal aldosterone content (RAC), aldosterone synthase expression, nuclear factor κB (NFκB), tumour necrosis factor α (TNFα), interleukin-6 (IL-6), transforming growth factor β (TGFβ), glomerular fibronectin, collagen type IV and urinary albumin extraction (UAE) in response to the aldosterone synthase inhibitor FAD286. Studies were conducted in adrenalectomized, normoglycaemic (control) or diabetic rats for 14 weeks. The FAD286 was administered during the last 10 weeks of the study. Plasma aldosterone levels were not detectable in any of the study groups. Compared with control rats, diabetic rats had higher levels of RAC by 488% (P < 0.01), NFκB by 293% (P < 0.01), TNFα by 356% (P < 0.01), IL-6 by 378% (P < 0.01), TGFβ by 337% (P < 0.01) and UAE by 1122% (P < 0.01), and increased glomerular fibronectin and collagen type IV immunostaining. In diabetic rats, FAD286 reduced RAC (P < 0.01), UAE (P < 0.05), NFκB mRNA, TNFα mRNA, IL-6 mRNA and TGFβ mRNA by 51, 41, 41 and 52% and also their proteins and decreased glomerular fibronectin and collagen type IV immunostaining. In conclusion, diabetes increases local aldosterone production in the kidney, which contributes to development of renal inflammation, matrix formation and albuminuria. Inhibition of aldosterone production in the kidney could be helpful in management of diabetic nephropathy.

Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis

“…38,39 Our recent study showed that high salt-induced kidney damage in KL(+/2) mice may involve activation of the MCP-1/CCR2 pathway and infiltration of T cells and macrophages. 16 Although we cannot exclude the contribution of hypertension to renal impairment in KL(+/2) mice, consistent results of other studies without the confounding interference of hypertension 7,40,41 suggest that the activated inflammatory process could play an independent and important role in renal damage.…”

“…Overproduction of aldosterone could impair kidney function and increase BP. 7,8 In this study, we investigated if haplodeficiency of KL(+/2) gene affects adrenal CYP11B2 expression and aldosterone synthesis.…”

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

“…[25][26][27][28] Inhibition of local renal aldosterone by FAD286 (aldosterone synthase inhibitor) or spironolactone (non-selective aldosterone receptor antagonist) has been shown to decrease nuclear factor kappaB (NFκB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), TGF-β1, glomerular fibronectin and collagen type IV expression in diabetic nephropathy. 29,30 Owing to these results, researchers concluded that local renal aldosterone contributes to development of renal inflammation, matrix formation and albuminuria, and therefore inhibition of aldosterone production in the kidney could be helpful in the management of diabetic nephropathy. 29,30 Evidence from the rat model of chronic CsA nephrotoxicity has shown that aldosterone receptor blockade effectively reduced TIF and completely prevented the reduction of the glomerular filtration rate, suggesting that aldosterone contributes to renal dysfunction and structure damage.…”

“…29,30 Owing to these results, researchers concluded that local renal aldosterone contributes to development of renal inflammation, matrix formation and albuminuria, and therefore inhibition of aldosterone production in the kidney could be helpful in the management of diabetic nephropathy. 29,30 Evidence from the rat model of chronic CsA nephrotoxicity has shown that aldosterone receptor blockade effectively reduced TIF and completely prevented the reduction of the glomerular filtration rate, suggesting that aldosterone contributes to renal dysfunction and structure damage. 31,32 The contribution of local renal aldosterone to chronic CsA nephrotoxicity remains to be elucidated.…”

Neutrophil-to-Lymphocyte Ratio as a Predictor of Worsening Renal Function in Diabetic Patients (3-Year Follow-Up Study)

“…8,9 Later, the role of inflammation and inflammatory cytokines in DN was studied over the last few years. [10][11][12][13][14][15][16] Inflammation secondary to ischemia and endothelial dysfunction was found to be associated with the development of DN. [17][18][19] Some medications were found to slow down the progression of DN through suggested antiinflammatory actions.…”