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

Supplementary Material for: Aldosterone Induces Kidney Fibroblast Proliferation via Activation of Growth Factor Receptors and PI3K/MAPK Signalling

<p><b><i>Background/Aims:</i></b> The mineralocorticoid hormone, aldosterone, has pro-fibrotic properties which can cause kidney damage. The severity of kidney interstitial fibrosis is dependent on the accumulation of fibroblasts, which result largely from local proliferation; however, it is unknown whether aldosterone stimulates kidney fibroblast proliferation. Therefore, we examined the effects of aldosterone on the proliferation of cultured kidney fibroblasts. <b><i>Methods:</i></b> Uptake of ³H-thymidine and cell number quantitation were used to determine the proliferative effects of aldosterone on a rat kidney fibroblast cell line (NRK49F cells) and interstitial fibroblasts extracted from mouse kidneys after unilateral ureter obstruction. The role of different mitogenic signalling pathways in aldosterone-induced proliferation was assessed using specific inhibitors of receptors and kinases. <b><i>Results:</i></b> Physiological levels of aldosterone induced a doubling of proliferation of kidney fibroblasts (p < 0.0001), which was inhibited by pre-treatment with the mineralocorticoid receptor antagonist, eplerenone. Aldosterone-induced fibroblast proliferation was dependent upon the kinase activity of growth factor receptors [platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor]. Notably, PDGF ligands were not involved in aldosterone-induced PDGFR activation, indicating receptor transactivation. Aldosterone-induced fibroblast proliferation also required signalling via PI3K, JNK and ERK pathways, but not via the transforming growth factor-β₁ receptor. <b><i>Conclusion:</i></b> Aldosterone ligation of the mineralocorticoid receptor in kidney fibroblasts results in rapid activation of growth factor receptors and induction of PI3K/MAPK signalling, which stimulates proliferation. This suggests that increased levels of aldosterone during disease may promote the severity of kidney fibrosis by inducing fibroblast proliferation.</p