Reduced podocyte expression of α3β1 integrins and podocyte depletion in patients with primary focal segmental glomerulosclerosis and chronic PAN-treated rats

Integrins attach cells to extracellular matrix (ECM) and mediate signals from ECM to cells or from cells to ECM. They regulate cell functions, including adhesion, migration, cell cycle regulation, and differentiation. Podocytes may detach from the glomerular basement membrane (GBM) and be excreted in the urine, and proteinuria is found in patients with primary focal segmental glomerulosclerosis (FSGS); both may be associated with loss of alpha 3 beta 1 integrins. In this study, we have examined the podocyte number in patients with primary FSGS and normal controls, and the alpha 3- and beta 1-integrin subunits expression of podocytes in patients with primary FSGS and chronic puromycin aminonucleoside (PAN)-treated rats by the morphometric, immunoperoxidase histochemical, and immunoelectron microscopic examination. We also measured their expression serially in rats that received repeated PAN injection. The results showed that the podocyte number was significantly decreased in patients with primary FSGS than in normal control (P < 0.05). The immunostaining score showed that both alpha 3- and beta 1 integrin subunits on podocytes in patients with primary FSGS were significantly lower than in normal controls (both P < 0.01). The number of immuno-gold particles of alpha 3- and beta 1-integrins at the effaced foot process area of patients with primary FSGS were also significantly decreased than that of normal controls (both P < 0.05). The immunostaining score of both alpha 3- and beta 1-integrin subunits was negatively correlated with the degree of glomerular sclerosing score and the amount of daily protein loss, and they were positively correlated with the number of podocytes. Chronic 12-week PAN-treated rats showed similar findings with decreased immunostaining expression and immuno-gold particles of alpha 3-integrin on podocytes than in normal control (both P < 0.05). The chronic PAN-treated rats also showed a trend toward gradually decreased immunostaining expression of a3-integrin subunit on podocyte during the progress from normal to FSGS state. These studies indicate that podocyte expression of alpha 3- and beta 1-integrin subunits is significantly reduced in humans with primary FSGS and chronic PAN-treated rats, before the morphological changes of FSGS are observed. The decreased podocyte expression of alpha 3 beta 1 integrins is closely related with podocyte depletion, glomerular sclerosis, and daily protein loss in patients with primary FSGS.