Dataset Information

FHL2 mediates podocyte Rac1 activation and foot process effacement in hypertensive nephropathy.

ABSTRACT: RAAS inhibition has been the standard treatment for CKD for years because it can reduce proteinuria and hence retard renal function decline, but the proteinuria reduction effect is still insufficient in many patients. Podocyte foot process and slit diaphragm are the final barrier to prevent serum proteins leak into urine, and podocyte foot process effacement is the common pathway of all proteinruic diseases. Cell structure are regulated by three evolutionarily conserved Rho GTPases, notably, Rac1 activation is sufficient and necessary for podocyte foot process effacement, however, Rac1 inhibition is not an option for kidney disease treatment because of its systemic side effects. Four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in podocytes and has been implicated in regulating diverse biological functions. Here, we used micro-dissected human kidney samples, in vitro podocyte culture experiments, and a hypertension animal model to determine the possible role of FHL2 in hypertensive nephropathy. FHL2 was abundantly upregulated in hypertensive human glomeruli and animal kidney samples. Genetic deletion of the FHL2 did not alter normal renal structure or function but mitigated hypertension-induced podocyte foot process effacement and albuminuria. Mechanistically, angiotensin II-induced podocyte cytoskeleton reorganization via FAK-Rac1 axis, FHL2 binds with FAK and is an important mediator of Ang II induced Rac1 activation, thus, FHL2 inhibition can selectively block FAK-Rac1 axis in podocyte and prevent proteinuria. These results provide important insights into the mechanisms of podocyte foot process effacement and points out a promising strategy to treat kidney disease.

SUBMITTER: Li SY

PROVIDER: S-EPMC6491468 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.

Dataset Information

FHL2 mediates podocyte Rac1 activation and foot process effacement in hypertensive nephropathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets