Expression of uPAR in Urinary Podocytes of Patients with Fabry Disease

Abstract

Background. Despite enzyme replacement therapy, Fabry nephropathy still progresses. Podocyturia is an irreversible event that antedates proteinuria and leads to chronic renal failure. We evaluated a potential mechanism of podocyte detachment via the expression of the urokinase-type Plasminogen Activator Receptor (uPAR) in urinary podocytes of Fabry patients. Methods. This is a cross-sectional study that included controls (n = 20) and Fabry patients (n = 44) either untreated (n = 23) or treated with agalsidase-β (n = 21). Variables. Variables are estimated glomerular filtration rate (eGFR), urinary protein : creatinine ratio, and urinary uPAR+ podocyte : creatinine ratio. uPAR mRNA expression in response to lyso-Gb3, a bioactive glycolipid accumulated in Fabry disease, was studied in cultured human podocytes. Results. Controls and Fabry patients had similar age, gender, and renal function. Urinary uPAR+ podocytes were higher in patients than in controls. Untreated patients were significantly younger; had more females, and presented lower urinary protein : creatinine ratios and significantly higher urinary uPAR+ podocytes than treated subjects. In treated patients, urinary uPAR+ podocytes correlated with urinary protein : creatinine ratio (ρ = 0.5; p = 0.02). Lyso-Gb3 at concentrations found in the circulation of Fabry patients increased uPAR expression in cultured podocytes. Conclusions. Urinary podocytes expressing uPAR are increased in Fabry patients, especially in untreated patients. The potential contribution of uPAR expression to podocyte detachment merits further studies.

Podocyturia: Potential applications and current limitations

“…In the case of IgA nephropathy, the number of uPAR + detached podocyte is significantly higher than controls and in patients with glomerular sclerotic lesions compared to those without (M1E0S1T0 vs M1E0S0T0 according to Oxford classification)[ 24 ]. Moreover, by western blot analysis as well as by PCR techniques we have confirmed the presence of elevated concentrations of uPAR in Fabry podocytes[ 23 ]. In this disease, we have found that urinary uPAR + podocytes are significantly higher in those without therapy[ 23 ].…”

“…Moreover, by western blot analysis as well as by PCR techniques we have confirmed the presence of elevated concentrations of uPAR in Fabry podocytes[ 23 ]. In this disease, we have found that urinary uPAR + podocytes are significantly higher in those without therapy[ 23 ]. Finally, in Fabry subjects increased levels of urinary αVβ3-integrins have been encountered[ 25 ].…”

“…In nephrotic urines, plasmin is elevated due to the upregulated action of uPA, and its receptor uPAR is highly expressed in urinary podocytes[ 21 , 22 ]. These findings suggest that uPAR is involved in podocyte detachment, probably via activation of αVβ3-integrin[ 16 , 23 , 24 ]. Employing immunofluorescent microscopy, we have demonstrated that in patients with IgA nephropathy and Fabry disease, uPAR is present in the cytoplasm of urinary podocytes.…”

“…In this regard, our group suggested that a probable pathway of podocyte detachment under pathological conditions is via the interaction between uPAR and αVβ3-integrins. This pathway may not be exclusive to one glomerulopathy, while more than one pathway could also be involved in one glomerular disease[ 23 ].…”

Fabry Disease

“…La biopsia renal es importante, dado que conoce determinar el daño estructural renal, al realizarla es necesario utilizar tinción de hematoxilina-eosina y azul de toluidina en el estudio de microscopia de luz y se recomienda guardar una muestra de tejido en glutaraldehído para practicar microscopía electrónica, si está disponible, para evidenciar compromiso en los podocitos y puede tener impacto en el pronóstico y en la decisión terapéutica 9,[46][47][48] .…”