The role of stress-activated protein kinase signaling in renal pathophysiology

Two major stress-activated protein kinases are the p38 mitogen-activated protein kinase (MAPK) and the c-Jun amino terminal kinase (JNK). p38 and JNK are widely expressed in different cell types in various tissues and can be activated by a diverse range of stimuli. Signaling through p38 and JNK is critical for embryonic development. In adult kidney, p38 and JNK signaling is evident in a restricted pattern suggesting a normal physiological role. Marked activation of both p38 and JNK pathways occurs in human renal disease, including glomerulonephritis, diabetic nephropathy and acute renal failure. Administration of small molecule inhibitors of p38 and JNK has been shown to provide protection from renal injury in different types of experimental kidney disease through inhibition of renal inflammation, fibrosis, and apoptosis. In particular, a role for JNK signaling has been identified in macrophage activation resulting in up-regulation of pro-inflammatory mediators and the induction of renal injury. The ability to provide renal protection by blocking either p38 or JNK indicates a lack of redundancy for these two signaling pathways despite their activation by common stimuli. Therefore, the stress-activated protein kinases, p38 and JNK, are promising candidates for therapeutic intervention in human renal diseases.

The role of stress-activated protein kinase signaling in renal pathophysiology.

Two major stress-activated protein kinases are the p38 mitogen-activated protein kinase (MAPK) and the c-Jun amino terminal kinase (JNK). p38 and JNK are widely expressed in different cell types in various tissues and can be activated by a diverse range of stimuli. Signaling through p38 and JNK is critical for embryonic development. In adult kidney, p38 and JNK signaling is evident in a restricted pattern suggesting a normal physiological role. Marked activation of both p38 and JNK pathways occurs in human renal disease, including glomerulonephritis, diabetic nephropathy and acute renal failure. Administration of small molecule inhibitors of p38 and JNK has been shown to provide protection from renal injury in different types of experimental kidney disease through inhibition of renal inflammation, fibrosis, and apoptosis. In particular, a role for JNK signaling has been identified in macrophage activation resulting in up-regulation of pro-inflammatory mediators and the induction of renal injury. The ability to provide renal protection by blocking either p38 or JNK indicates a lack of redundancy for these two signaling pathways despite their activation by common stimuli. Therefore, the stress-activated protein kinases, p38 and JNK, are promising candidates for therapeutic intervention in human renal diseases.

Wave and sediment dynamics along a shallow subtidal sandy beach inhabited by modern stromatolites.

To help define the habitat of modern marine stromatolites, wave-dominated flow and sediment transport were studied in the shallow subtidal region (1-2 m depth) along the slightly concave, windward face of Highborne Cay, Exuma, Bahamas - the only face of the cay that includes a population of stromatolites concentrated near the region of highest curvature of the beach. Wave energy impacting this island's most exposed beach was driven by local wind forcing which increases largely in response to the passage of atmospheric disturbances that typically affect the region for periods of a few days. Although some wave energy is almost always noted (maximum horizontal orbital speeds at the bottom are rarely <10 cm s(-1)), wave conditions remain comparatively calm until local winds increase above speeds of approximately 3-4 m s(-1) at which point maximum wave speeds rapidly increase to 50-80 cm s(-1). Stromatolites, which are largely restricted to the shoreward side of a shallow platform reef, are sheltered by the reef beyond which wave speeds are one to four times higher (depending on tidal stage). Moreover, stromatolite populations are predominantly found along a region of this wave-exposed beach that experiences comparatively reduced wave energy because of the curved morphology of the island's face. Maximum wave speeds are 1.4 to 2 times higher along more northern sections of the beach just beyond the locus of stromatolite populations. A quantitative model of sediment transport was developed that accurately predicted accumulation of suspended sediment in sediment traps deployed in the shallow subtidal zone along this beach. This model, coupled with in situ wave records, indicates that gross rates of suspended sediment deposition should be two to three times higher northward of the main stromatolite populations. Regions of the beach containing stromatolites nevertheless should experience significant rates of gross suspended sediment deposition averaging 7-10 g cm(-2) day(-1) ( approximately 4-6 cm day(-1)). Results suggest that one axis of the habitat of modern marine stromatolites may be defined by a comparatively narrow range of flow energy and sediment transport conditions.