No abstract

Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis, diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53Ser15 phosphorylation with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGF-β1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGF-β1 treatment and PTEN silencing potentiated epithelial cell death via p53 dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction with accompanying PAI-1 dependent proliferative arrest, and cooperates with TGF-β1 to induce the expression of profibrotic genes and tubular apoptosis.

Surgery is the most efficacious treatment for postprostatectomy incontinence. The ideal surgical approach depends on a variety of patient factors including history of prior incontinence surgery or radiation treatment, bladder contractility, severity of leakage, and patient expectations. Most patients choose to avoid a mechanical device, opting for the male sling over the artificial urinary sphincter. The modern male sling has continued to evolve with respect to device design and surgical technique. Various types of slings address sphincteric incompetence via different mechanisms of action. The recommended surgery, however, must be individualized to the patient based on degree of incontinence, detrusor contractility, and urethral compliance. A thorough urodynamic evaluation is indicated for the majority of patients, and the recommendation for an artificial urinary sphincter, a transobturator sling, or a quadratic sling will depend on urodynamic findings and the patient's particular preference. As advancements in this field evolve, and our understanding of the pathophysiology of incontinence and mechanisms of various devices improves, we expect to see continued evolution in device design.

Protein phosphatase magnesium-dependent-1A (PPM1A) dephosphorylates SMAD2/3, which suppresses TGF-β signaling in keratinocytes and during Xenopus development; however, potential involvement of PPM1A in chronic kidney disease is unknown. PPM1A expression was dramatically decreased in the tubulointerstitium in obstructive and aristolochic acid nephropathy, which correlates with progression of fibrotic disease. Stable silencing of PPM1A in human kidney-2 human renal epithelial cells increased SMAD3 phosphorylation, stimulated expression of fibrotic genes, induced dedifferentiation, and orchestrated epithelial cell-cycle arrest via SMAD3-mediated connective tissue growth factor and plasminogen activator inhibitor-1 up-regulation. PPM1A stable suppression in normal rat kidney-49 renal fibroblasts, in contrast, promoted a SMAD3-dependent connective tissue growth factor and plasminogen activator inhibitor-1-induced proliferative response. Paracrine factors secreted by PPM1A-depleted epithelial cells augmented fibroblast proliferation (>50%) compared with controls. PPM1A suppression in renal cells further enhanced TGF-β1-induced SMAD3 phosphorylation and fibrotic gene expression, whereas PPM1A overexpression inhibited both responses. Moreover, phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A, which enhanced SMAD3-mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression. Thus, phosphate tensin homolog on chromosome 10 is an upstream regulator of renal PPM1A deregulation. These findings establish PPM1A as a novel repressor of the SMAD3 pathway in renal fibrosis and as a new therapeutic target in patients with chronic kidney disease.-Samarakoon, R., Rehfuss, A., Khakoo, N. S., Falke, L. L., Dobberfuhl, A. D., Helo, S., Overstreet, J. M., Goldschmeding, R., Higgins, P. J. Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.

The "real world" success rates for staged SNS implantation in California are less than those observed by some academic centers of excellence but better than previously reported for Medicare beneficiaries. Successful trial rates for interstitial cystitis and neurogenic voiding dysfunction are similar to refractory overactive bladder.