Pathophysiology of renal tubular obstruction: Therapeutic role of synthetic RGD peptides in acute renal failure

In his famous work On the Natural Faculties, Galen of Pergamum introduced the idea of “attraction” [δλκηζ] as the principal mode of kidney function: the attraction of blood to the kidney, he claimed, results in the production of urine [1]. Though unproven in Galen's ancient times and entirely rejected by the later generations as a mechanistic explanation of renal function, the concept of attraction has not only survived, albeit in a modified form, but has become one of the cornerstone principles of modern physiology and our current understanding of the pathophysiology of processes as diverse as platelet aggregation, metastases, immune recognition and wound healing, to name a few, all of which are governed by adhesion molecules. Here we review the role of adhesion molecules in the pathophysiology of tubular obstruction, focusing on the integrins and their newly recognized function in it.The importance of renal tubular obstruction in the pathogenesis of acute renal failure (ARF) was brought to center stage by a series of elegant microdissection studies by Oliver, MacDowell and Tracy [2]. Using servo-null pressure monitoring of the proximal tubular pressure in diverse models of ARF, investigators have provided solid evidence for the elevation in hydrostatic intratubular pressure concomitant with the unchanged stop-flow and estimated glomerular capillary pressures, further confirming the tubulo-obstructive component of this syndrome [3–5]. It has been concluded, therefore, that tubular obstruction and elevated proximal tubular pressure equilibrate glomerular filtration pressure, thus leading to the persisting oliguria. Necrotic epithelial cells have been postulated to provide the matrix for casts obstructing the tubular lumen. Recent findings of viable epithelial cells in the urine of patients and experimental animals with ARF, however, cast doubt on the postulated schema and suggest the possibility of epithelial cell detachment as an important contributor to the development of tubular obstruction [6–8].In the following discussion we develop this theme, providing data on the possible mechanism(s) of tubular obstruction in ischemic ARF, and on the therapeutic strategies in and benefits of inhibiting tubular obstruction, and suggest some future directions of this fledgling field of investigations

Transforming Growth Factor: β Signaling Is Essential for Limb Regeneration in Axolotls

Axolotls (urodele amphibians) have the unique ability, among vertebrates, to perfectly regenerate many parts of their body including limbs, tail, jaw and spinal cord following injury or amputation. The axolotl limb is the most widely used structure as an experimental model to study tissue regeneration. The process is well characterized, requiring multiple cellular and molecular mechanisms. The preparation phase represents the first part of the regeneration process which includes wound healing, cellular migration, dedifferentiation and proliferation. The redevelopment phase represents the second part when dedifferentiated cells stop proliferating and redifferentiate to give rise to all missing structures. In the axolotl, when a limb is amputated, the missing or wounded part is regenerated perfectly without scar formation between the stump and the regenerated structure. Multiple authors have recently highlighted the similarities between the early phases of mammalian wound healing and urodele limb regeneration. In mammals, one very important family of growth factors implicated in the control of almost all aspects of wound healing is the transforming growth factor-beta family (TGF-β). In the present study, the full length sequence of the axolotl TGF-β1 cDNA was isolated. The spatio-temporal expression pattern of TGF-β1 in regenerating limbs shows that this gene is up-regulated during the preparation phase of regeneration. Our results also demonstrate the presence of multiple components of the TGF-β signaling machinery in axolotl cells. By using a specific pharmacological inhibitor of TGF-β type I receptor, SB-431542, we show that TGF-β signaling is required for axolotl limb regeneration. Treatment of regenerating limbs with SB-431542 reveals that cellular proliferation during limb regeneration as well as the expression of genes directly dependent on TGF-β signaling are down-regulated. These data directly implicate TGF-β signaling in the initiation and control of the regeneration process in axolotls

Heat shock protein 27 is the major differentially phosphorylated protein involved in renal epithelial cellular stress response and controls focal adhesion organization and apoptosis

We used two-dimensional difference gel electrophoresis to determine early changes in the stress-response pathways that precede focal adhesion disorganization linked to the onset of apoptosis of renal epithelial cells. Treatment of LLC-PK1 cells with the model nephrotoxicant 1,2-(dichlorovinyl)-L-cysteine ( DCVC) resulted in a > 1.5-fold up- and down-regulation of 14 and 9 proteins, respectively, preceding the onset of apoptosis. Proteins included those involved in metabolism, i.e. aconitase and pyruvate dehydrogenase, and those related to stress responses and cytoskeletal reorganization, i.e. cofilin, Hsp27, and alpha-b-crystallin. The most prominent changes were found for Hsp27, which was related to a pI shift in association with an altered phosphorylation status of serine residue 82. Although both p38 and JNK were activated by DCVC, only inhibition of p38 with SB203580 reduced Hsp27 phosphorylation, which was associated with accelerated reorganization of focal adhesions, cell detachment, and apoptosis. In contrast, inhibition of JNK with SP600125 maintained cell adhesion as well as protection against apoptosis. Active JNK co-localized at focal adhesions after DCVC treatment in a FAK-dependent manner. Inhibition of active JNK localization at focal adhesions did not prevent DCVC-induced phosphorylation of Hsp27. Overexpression of a phosphorylation-defective mutant Hsp27 acted as a dominant negative and accelerated the DCVC-induced changes in the focal adhesions as well as the onset of apoptosis. Our data fit a model whereby early p38 activation results in a rapid phosphorylation of Hsp27, a requirement for proper maintenance of cell adhesion, thus suppressing renal epithelial cell apoptosis