The transmission of elevated blood pressure to the glomerulus and pressure-induced glomerular injury play central roles in the pathogenesis of kidney disease and its progression to end-stage renal failure. The renal afferent arteriole sets the pre-glomerular resistance and pressure-induced or 'myogenic' afferent arteriolar vasoconstriction is a primary mechanism protecting the glomerulus from the damaging effects of hypertension. The systolic pressure, being the highest level of pressure attained and most frequent pressure oscillation impacting on the renal vasculature, potentially represents the most damaging component of the blood pressure. Indeed, recent studies indicate that elevations in systolic blood pressure are more closely linked to kidney disease than are elevations in diastolic pressure. However, the current view, derived from dynamic studies of autoregulation, is that the renal vasculature responds passively to pressure signals presented at rates exceeding the myogenic operating frequency (0.2-0.3 Hz in the rat). Thus existing concepts do not explain the mechanisms that normally protect the kidney from elevations in the systolic pressure which are presented at the heart rate (6 Hz in the rat). A recent study from our laboratory addressed this issue. Using a modelling approach and direct measurements of myogenic responses, we found that the afferent arteriole is able to sense and appropriately adjust tone in response to changes in systolic pressure, presented at the heart rate. Key kinetic attributes allowing this vessel to respond in this manner appear to be a very short delay in activation, an unusually rapid rate of vasoconstriction and a longer delay in vasodilation. The present review summarizes this work and presents recent findings addressing the determinants of the myogenic vasoconstriction in the afferent arteriole.

Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools.  In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway.  Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumor of proliferating germline stem cells.  Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers.  We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic-reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations.  We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations.  Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR.  Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.