Aldosterone is involved in the pathogenesis of obesity-related glomerulopathy through activation of Wnt/β-catenin signaling in podocytes

Abstract

Obesity-related glomerulopathy (ORG) is morphologically characterized by glomerulomegaly with or without observable focal segmental glomerulosclerosis under light microscope, with decreased podocyte density and number, and with increased foot‑process width observed under electron microscope. The severity of podocyte injury is correlated with the degree of proteinuria and renal dysfunction. However, the pathogenesis of ORG is not well understood. The aim of the present study was to explore the possible pathogenic role of aldosterone (ALDO) in ORG. In the in vivo animal experiments, body weight, Lee's obesity index, abdominal fat index, urinary protein excretion, average glomerular diameter were significantly increased, the mRNA and protein expression of podocyte‑associated molecules including nephrin, podocin, podoplanin and podocalyxin were significantly reduced, and the Wnt/β‑catenin signaling pathway was activated in ORG model mice compared with the Control mice, whereas the administration of spironolactone significantly ameliorated these effects. In the in vitro experiments on cultured podocytes, the mRNA and protein expression levels of the aforementioned podocyte‑associated molecules were significantly downregulated and the Wnt/β‑catenin signaling pathway was activated following ALDO stimulation, whereas eplerenone significantly attenuated all the above effects. Dickkopf‑related protein 1 (DKK1), an inhibitor of Wnt/β‑catenin signaling pathway, also reduced the effects of ALDO exposure on the expression of podocyte‑associated molecules. The present study hypothesized that ALDO may be involved in the pathogenesis of ORG through the activation of Wnt/β‑catenin signaling pathway in podocytes.

No Significant Role for Smooth Muscle Cell Mineralocorticoid Receptors in Atherosclerosis in the Apolipoprotein-E Knockout Mouse Model

“…Potential mechanisms for this reduction in body weight with SMC-specific MR deletion are unclear. While aldosterone and MR signaling have been implicated in the components of the metabolic syndrome associated with obesity ( 52 , 53 ), and MR blockade prevents obesity-induced metabolic syndrome in some animal models ( 54 , 55 ), this relationship has not held true in human studies ( 56 – 58 ). Further, to our knowledge, no data currently exists linking SMC-specific MR to the development of obesity and metabolic syndrome.…”

Obesity-Related Glomerulopathy: A Latent Change in Obesity Requiring More Attention

“…Third, Ang II binds to mineralocorticoid receptors directly, facilitating sodium and water reabsorption [28]. Furthermore, the increased aldosterone in the setting of obesity generates reactive oxygen species which injures podocytes and causes kidney dysfunction [29] (Fig. 1).…”

Aldosterone Contributed to Pulmonary Arterial Hypertension Development via Stimulating Aquaporin Expression and Pulmonary Arterial Smooth Muscle Cells Proliferation

“…In addition, similarly to the results in the PAH rat model, SP downregulated the expressions of AQP1 as well as β-catenin in PASMCs dealt with ALDO. Zhu et al [41] mentioned that ALDO was associated with obesityrelated glomerulopathy via β-catenin in podocytes. Thus, we speculated that when PAH was triggered, AQP1 and β-catenin act as 2 critical factors through which SP exerted its regulatory role.…”