Integrin-ß1 is required for the renal cystogenesis caused by ciliary defects.

Defects in the function of primary cilia are commonly associated with the development of renal cysts. On the other hand, the intact cilium appears to contribute a cystogenic signal whose effectors remain unclear. As integrin-ß1 is required for the cystogenesis caused by the deletion of the polycystin 1 gene, we asked whether it would be similarly important in the cystogenetic process caused by other ciliary defects. We addressed this question by investigating the effect of integrin-ß1 deletion in a ciliopathy genetic model in which the Ift88 gene, a component of complex B of intraflagellar transport that is required for the proper assembly of cilia, is specifically ablated in principal cells of the collecting ducts. We showed that the renal cystogenesis caused by loss of Ift88 is prevented when integrin-ß1 is simultaneously depleted. In parallel, pathogenetic manifestations of the disease, such as increased inflammatory infiltrate and fibrosis, were also significantly reduced. Overall, our data indicate that integrin-ß1 is also required for the renal cystogenesis caused by ciliary defects and point to integrin-ß1-controlled pathways as common drivers of the disease and as possible targets to interfere with the cystogenesis caused by ciliary defects.

Inactivation of integrin-ß1 prevents the development of polycystic kidney disease after the loss of polycystin-1.

Dysregulation of polycystin-1 (PC1) leads to autosomal dominant polycystic kidney disease (ADPKD), a disorder characterized by the formation of multiple bilateral renal cysts, the progressive accumulation of extracellular matrix (ECM), and the development of tubulointerstitial fibrosis. Correspondingly, cystic epithelia express higher levels of integrins (ECM receptors that control various cellular responses, such as cell proliferation, migration, and survival) that are characteristically altered in cystic cells. To determine whether the altered expression of ECM and integrins could establish a pathologic autostimulatory loop, we tested the role of integrin-ß1 in vitro and on the cystic development of ADPKD in vivo. Compared with wild-type cells, PC1-depleted immortalized renal collecting duct cells had higher levels of integrin-ß1 and fibronectin and displayed increased integrin-mediated signaling in the presence of Mn(2+). In mice, conditional inactivation of integrin-ß1 in collecting ducts resulted in a dramatic inhibition of Pkd1-dependent cystogenesis with a concomitant suppression of fibrosis and preservation of normal renal function. Our data provide genetic evidence that a functional integrin-ß1 is required for the early events leading to renal cystogenesis in ADPKD and suggest that the integrin signaling pathway may be an effective therapeutic target for slowing disease progression.

Collapsing glomerulopathy in 19 patients with systemic lupus erythematosus or lupus-like disease.

BACKGROUND AND OBJECTIVES: Collapsing glomerulopathy is a podocytopathy with segmental or global wrinkling and collapse of capillary walls and overlying epithelial cell proliferation. Idiopathic collapsing glomerulopathy is a distinct clinicopathologic entity with significant proteinuria, poor response to immunosuppressive therapy, and rapid progression to renal failure. Collapsing glomerulopathy is associated with viral infections, autoimmune disease, and drugs. This work presents the largest group of collapsing glomerulopathy in patients with SLE. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Clinicopathological features were retrospectively studied in 19 patients with SLE (16 patients) or SLE-like (3 patients) disease with collapsing glomerulopathy. RESULTS: Initially, 95% of patients had nephrotic syndrome with proteinuria of 3-12 g per 24 hours, creatinine levels of 0.6-9.6 mg/dl, positive lupus serologies, and normal complement levels in 63%. Segmental and/or global collapsing glomerulopathy was seen in 11%-77% of glomeruli. Tubular atrophy with focal microcystic changes and interstitial fibrosis was seen in 35% of patients. Minimal glomerular mesangial deposits were noted in 63% of patients, and extensive foot process effacement was seen in 82% of patients. Initial treatment was with pulse/oral steroids. Follow-up from 13 patients revealed that 7 patients progressed to ESRD at the time of biopsy up to 21 months later, 1 patient returned to normal creatinine (1.1 mg/dl) without proteinuria, and 5 patients had creatinine of 1.2-3.6 mg/dl with proteinuria of 0.37-4 g per 24 hours. CONCLUSIONS: Collapsing glomerulopathy may be seen in SLE patients presenting with massive proteinuria with or without lupus nephritis, which may have prognostic significance.