Renal p38 MAP kinase activity in experimental diabetes

Abstract

Renal cell activity of p38 mitogen-activated protein kinase (p38) is increased in the diabetic milieu. p38 mediates signals relevant for the development of diabetic nephropathy (DN). However, renal p38 in Type 1 diabetes in vivo, particularly in conditions reflecting the differences in metabolic control, and its activity in advanced stages of DN, has received less attention. We examined the p38 pathway in renal cortex of rats with streptozotocin diabetes (4 weeks) with poor (DS), moderate (DM), and intensive (DII) metabolic control, achieved by varying doses of insulin therapy. Renal p38 was also studied in 12-month diabetic rats with established nephropathy (DM12) and compared with age-matched controls. p38 activity (in vitro kinase assay and expression of phosphorylated (active) p38 (P-p38)) was increased in DM and DS rats, as compared with non-diabetic controls, and attenuated by intensive insulin treatment. In all groups, P-p38 was predominantly localized in macula densa cells. Diabetic rats also demonstrated P-p38 immunoreactivity in the distal tubule and glomeruli. Enhanced p38 activity in DS and DM rats was not associated with increases in expression of active mitogen-activated protein kinase 3/6, an activator of p38, but paralleled with increased expression of scaffolding protein transforming growth factor-b-activated protein kinase 1-binding protein 1. Expression of mitogen-activated protein phosphatase-1 (MKP-1), one of the phosphatases involved in inactivation of mitogen-activated protein kinase signaling, was increased in all diabetic groups, irrespective of metabolic control. Renal p38 activation was also detectable in D12 rats with established albuminuria and glomerulosclerosis. In summary, renal cortical p38 activity was increased in diabetic rats at early and advanced stages of nephropathy, as compared with non-diabetic animals, and attenuated by improved metabolic control. p38 activation in diabetes is likely to occur via multiple pathways and cannot be explained by downregulation of MKP-1. KEYWORDS: diabetic nephropathy; hyperglycemia; p38 mitogen-activated protein kinase; proteinuria; signaling High glucose concentrations, and potentially other factors in the diabetic milieu, trigger pathophysiological signals mediated by the activation of specific kinase cascades. Altered activation of mitogen-activated protein (MAP) kinases (MAPK) occurs under these conditions and results in a broad spectrum of acute and long-term effects including mobilization of intracellular calcium and induction of gene expression. 1 In the kidney, such aberrant activation of MAPK cascades may perturb the balance of humoral and cytokine systems responsible for regulating vascular tone, permeability, renal cellular growth, and composition of the extracellular/mesangial matrix (ie, factors associated with the development of diabetic nephropathy). 2,3 p38 mitogen-activated protein kinase (p38), a member of the MAPK family, is activated by a number of stimuli. As a stress-activated kinase, p38 is activated by physical and ch...

Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release

“…p38 MAPK, a member of the MAPK family, is activated by physical and chemical stress factors, inflammatory cytokines, and both vasoactive and growth factors. 7 At the early stages of experimental diabetic nephropathy, active p38 has previously been localized in the JGA area 25,26 and in the distal tubules. 26 Consistent with these findings, immunohistochemistry showed that MD cells and adjacent portions of the distal nephron are the major sites of active p38 expression in the diabetic kidney.…”

“…26 Consistent with these findings, immunohistochemistry showed that MD cells and adjacent portions of the distal nephron are the major sites of active p38 expression in the diabetic kidney. 7 Moreover, it has been found that ERK1/2 is generally but not exclusively responsive to activators of both receptor tyrosine kinases and G protein-coupled receptors. 27 In addition, succinate activated ERK in GPR91-transfected cells (293-hGPR91).…”

ASK1 Inhibitor Halts Progression of Diabetic Nephropathy in Nos3-Deficient Mice

“…The diabetic kidney is stressed by multiple factors including hyperglycemia, reactive oxygen species, advanced glycation end products, proinflammatory cytokines, and angiotensin II-all of which can induce signaling via the p38 mitogen-activated protein kinase (MAPK) (2)(3)(4)(5). Increased activation of p38 MAPK in glomeruli and the tubulointerstitial compartment has been described in animal models of diabetic nephropathy as well as in patients with diabetic nephropathy (6)(7)(8)(9). Inhibition of p38 MAPK activation via pharmacologic and genetic approaches can suppress the induction of albuminuria, glomerular matrix expansion, and inflammation in models of type 1 and type 2 diabetic nephropathy (9,10), although intervention studies in established disease are lacking.…”

Early intensive insulin therapy attenuates the p38 pathway in the renal cortex and indices of nephropathy in diabetic rats

“…Clinical trials have been shown the beneficial effects of intensive insulin therapy on diabetic microvascular complications [17][18]. Recent rodent study indicated that renal cortical p38 activity increased in diabetic rats but was attenuated by improved glycemic control achieved by insulin therapy [5]. However, that study was performed in type 1 diabetes rodent model and did not investigate the effects of late insulin therapy.…”

“…P38 MAPK was activated in vivo in glomeruli from diabetic rats and in vitro in mesangial cells exposed to high glucose [3][4]. Moreover, increased renal cortical p38 MAPK activity in diabetic rats could be attenuated by intensive (blood glucose=172 ± 10 mg/dL) but not poor or moderate metabolic control [5]. Therefore, attenuation of the p38 MAPK pathway in the renal cortex could be one beneficial effect of intensive insulin therapy.…”