nach oben

Diabetologia

Erschienen in:

01.07.2004 | Article

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

Erschienen in: Diabetologia | Ausgabe 7/2004

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Inflammation and fibrosis are pathological mechanisms that are partially regulated by cell signalling through the p38 mitogen-activated protein kinase (MAPK) pathway. Elements of the diabetic milieu such as high glucose and advanced glycation end-products induce activation of this pathway in renal cells. Therefore, we examined whether p38 MAPK signalling is associated with the development of human and experimental diabetic nephropathy.

Methods

Immunostaining identified phosphorylated (active) p38 MAPK in human biopsies with no abnormality (n=6) and with Type 2 diabetic nephropathy (n=12). Changes in kidney levels of phosphorylated p38 were assessed by immunostaining and western blotting in mice with streptozotocin-induced Type 1 diabetes that had been killed after 0.5, 2, 3, 4 and 8 months, and in Type 2 diabetic db/db mice at 2, 4, 6 and 8 months of age.

Results

Phosphorylated p38 was detected in some intrinsic cells in normal human kidney, including podocytes, cortical tubules and occasional interstitial cells. Greater numbers of these phosphorylated p38+ cells were observed in diabetic patients, and phosphorylated p38 was identified in accumulating interstitial macrophages and myofibroblasts. A similar pattern of p38 activation was observed in both mouse models of diabetes. In mice, kidney levels of phosphorylated p38 increased (2–6 fold) following the onset of Type 1 and Type 2 diabetes. In both mouse models, interstitial phosphorylated p38+ cells were associated with hyperglycaemia, increased HbA₁c levels and albuminuria. Further assessment of streptozotocin-induced diabetic nephropathy showed that interstitial phosphorylated p38+ cells correlated with interstitial fibrosis (myofibroblasts, collagen).

Conclusions/interpretation

Increased p38 MAPK signalling is a feature of human and experimental diabetic nephropathy. Time course studies in mouse models suggest that phosphorylation of p38 plays a pathological role, particularly in the development of interstitial fibrosis.

Ritz E, Tarng DC (2001) Renal disease in type 2 diabetes. Nephrol Dial Transplant 16 [Suppl 5]:11–18CrossRefPubMed

Keane WF, Lyle PA (2003) Recent advances in the management of type 2 diabetes and nephropathy: lessons from the RENAAL study. Am J Kidney Dis 41 [3 Suppl 1]:S22–S25CrossRefPubMed

Remuzzi G, Bertani T (1998) Pathophysiology of progressive nephropathies. N Engl J Med 339:1448–1456CrossRefPubMed

Raigeaud J, Gupta S, Rogers JS et al. (1995) Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 270:7420–7426CrossRef

Rovin BH, Wilmer WA, Danne M, Dickerson JA, Dixon CL, Lu L (1999) The mitogen activated protein kinase p38 is necessary for interleukin 1beta-induced monocyte chemoattractant protein 1 expression by human mesangial cells. Cytokine 11:118–126CrossRefPubMed

Guan Z, Buckman SY, Miller BW, Springer LD, Morrison AR (1998) Interleukin-1beta-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat mesangial cells. J Biol Chem 273:28670–28676CrossRefPubMed

Chin BY, Mohsenin A, Li SX, Choi AM, Choi ME (2001) Stimulation of pro-alpha(1) (I) collagen by TGF-beta(1) in mesangial cells: role of the p38 MAPK pathway. Am J Physiol Renal Physiol 280:F495–F504PubMed

Kucich U, Rosenbloom JC, Shen G et al. (2000) TGF-beta1 stimulation of fibronectin transcription in cultured human lung fibroblasts requires active geranylgeranyl transferase 1, phosphatidylcholine-specific lipase C, protein kinase C-delta, and p38, but not erk1/erk2. Arch Biochem Biophys 374:313–324CrossRefPubMed

Branger J, van den Blink B, Weijer S et al. (2002) Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol 168:4070–4077CrossRefPubMed

10.

Wada T, Furuichi K, Sakai N et al. (2001) Involvement of p38 mitogen-activated protein kinase followed by chemokine expression in crescentic glomerulonephritis. Am J Kidney Dis 38:1169–1177CrossRefPubMed

11.

Stambe C, Atkins RC, Tesch GH et al. (2003) Blockade of p38α MAPK ameliorates inflammatory renal injury in rat anti-GBM glomerulonephritis. J Am Soc Nephrol 14:338–351CrossRefPubMed

12.

Underwood DC, Osborn RR, Bochnowicz S et al. (2000) SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol 279:L895–L902PubMed

13.

Badger AM, Griswold DE, Kapadia R et al. (2000) Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum 43:175–183CrossRefPubMed

14.

Wilmer WA, Dixon CL, Herbert C (2001) Chronic exposure of human mesangial cells to high glucose environments activates the p38 MAPK pathway. Kidney Int 60:858–871CrossRefPubMed

15.

Daoud S, Schinzel R, Neumann A et al. (2001) Advanced glycation end products: activators of cardiac remodelling in primary fibroblasts from adult rat hearts. Mol Med 7:543–551PubMedPubMedCentral

16.

Yamakawa T, Tanak S, Yamakawa Y et al. (1995) Augmented production of tumour necrosis factor-alpha in obese mice. Clin Immunol Immunopathol 75:51–56CrossRefPubMed

17.

Hong SW, Isono M, Chen S, Iglesias-De La Cruz MC, Han DC, Ziyadeh FN (2001) Increased glomerular and tubular expression of transforming growth factor-beta 1, its type II receptor, and activation of the SMAD signaling pathway in the db/db mouse. Am J Pathol 158:1653–1663CrossRefPubMed

18.

Azar ST, Salti I, Zantout MS, Major S (200) Alterations in plasma transforming growth factor beta in normo-albuminuric type 1 and type 2 diabetic patients. J Clin Endocrinol Metab 85:4680–4682

19.

Yeh CH, Sturgis L, Haidacher J et al. (2001) Requirement of p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear-kB transcriptional activation and cytokine secretion. Diabetes 50:1495–1504CrossRefPubMed

20.

Hsu HY, Chiu SL, Wen MH, Chen KY, Hua KF (2001) Ligands of macrophage scavenger receptor induce cytokine expression via differential modulation of protein kinase signalling pathways. J Biol Chem 276:28719–28730CrossRefPubMed

21.

Leonard M, Ryan MP, Watson AJ, Schramek H, Healy E (1999) Role of MAP kinase pathways in mediating IL-6 production in human primary mesangial and proximal tubular cells. Kidney Int 56:1366–1377CrossRefPubMed

22.

Weigert C, Sauer U, Brodbeck K, Pfeiffer A, Haring HU, Schleicher ED (2000) AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-beta1 promoter in mesangial cells. J Am Soc Nephrol 11:2007–2016PubMed

23.

Gruden G, Zonca S, Hayward A et al. (2000) Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent. Diabetes 49:655–661CrossRefPubMed

24.

Kang SW, Adler SG, Lapage J, Natarajan R (2001) p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli. Kidney Int 60:543–552CrossRefPubMed

25.

Jackson AE, Atkins RC, Glasgow EF (1991) Ultrastructural localization of human kidney antigens using monoclonal antibodies. Histochem J 23:509–516CrossRefPubMed

26.

Lan HY, Mu W, Nikolic-Paterson DJ, Atkins RC (1995) A novel, simple, reliable, and sensitive method for multiple immuno-enzyme labeling: use of microwave oven heating to block antibody crossreactivity and retrieve antigens. J Histochem Cytochem 43:97–102CrossRefPubMed

27.

Tian W, Zhang Z, Cohen DM (2000) MAPK signalling in the kidney. Am J Physiol Renal Physiol 279:F593–F604PubMed

28.

Huber TB, Kottgen M, Schilling B, Walz G, Benzing T (2001) Interaction with podocin facilitates nephrin signaling. J Biol Chem 276:41543–41546CrossRefPubMed

29.

Tsiani E, Lekas P, Fantus IG, Dlugosz J, Whiteside C (2002) High glucose-enhanced activation of mesangial cell p38 MAPK by ET-1, ANG II, and platelet-derived growth factor. Am J Physiol Endocrinol Metab 282:E161–E169PubMed

30.

Muller E, Burger-Kentischer A, Neuhofer W et al. (1999) Possible involvement of heat shock protein 25 in the angiotensin II-induced glomerular mesangial cell contraction via p38 MAP kinase. J Cell Physiol 181:462–469CrossRefPubMed

31.

Sorokin A, Forshi M, Dunn MJ (2002) Endothelin signalling and regulation of protein kinases in glomerular mesangial cells. Clin Sci 103 [Suppl 48]:132S–136SCrossRef

32.

Goruppi S, Bonventre JV, Kyriakis JM (2002) Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertrophy. EMBO J 21:5427–5436CrossRefPubMedPubMedCentral

33.

Weigert C, Brodbeck K, Klopfer K, Haring HU, Schleicher ED (2002) Angiotensin II induces human-TGF-beta 1 promoter activation: similarity to hyperglycaemia. Diabetologia 45:890–898CrossRefPubMed

34.

Wu CH, Huang CM, Lin CH, Ho YS, Chen CM, Lee HM (2002) Advanced glycosylation end products induce NF-kappaB dependent iNOS expression in RAW 264.7 cells. Mol Cell Endocrinol 194:9–17CrossRefPubMed

35.

Huwiler A, Pfeilschifter J (1999) Nitric oxide stimulates the stress-activated protein kinase p38 in rat mesangial cells. J Exp Biol 202:655–660PubMed

36.

Guan Z, Buckman SY, Springer LD, Morrison AR (1999) Both p38alpha(MAPK) and JNK/SAPK pathways are important for induction of nitric oxide synthase by interleukin-1 beta in rat glomerular mesangial cells. J Biol Chem 274:3600–3606

37.

Hsieh TJ, Zhang SL, Filep JG, Tang SS, Ingelfinger JR, Chan JS (2002) High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. Endocrinology 143:2975–2985CrossRefPubMed

38.

Hsieh TJ, Fustier P, Zhang SL et al. (2003) High glucose stimulates angiotensinogen gene expression and cell hypertrophy via activation of the hexosamine biosynthesis pathway in rat kidney proximal tubular cells. Endocrinology 144:4338–4349CrossRefPubMed

39.

Sheikh-Hamad D, Di Mari J, Suki WN, Safirstein R, Watts BA 3^rd, Rouse D (1998) p38 kinase activity is essential for osmotic inductions of mRNAs for HSP70 and transporter for organic solute betaine in Madin-Darby canine kidney cells. J Biol Chem 273:1832–1837CrossRefPubMed

40.

Meldrum KK, Meldrum DR, Hile KL et al. (2001) p38 MAPK mediates renal tubular cell TNF-α production and TNF-alpha-dependent apoptosis during simulated ischemia. Am J Physiol Cell Physiol 281:C563–C570PubMed

41.

Zhang M, Tang JW, Li XM (2003) Interleukin-1beta-induced transdifferentiation of renal proximal tubular cells is mediated by p38-mitogen-activated protein kinase phosphorylation. Zhonghua Yi Xue Za Zhi 83:1161–1165

42.

Essawy M, Soylemezoglu O, Muchaneta-Kubara EC et al. (1997) Myofibroblasts and the progression of diabetic nephropathy. Nephrol Dial Transplant 12:43–50CrossRefPubMed

43.

Maher P (1999) p38 mitogen-activated protein kinase activation is required for fibroblast growth factor-2-stimulated cell proliferation but not differentiation. J Biol Chem 274:17491–17498CrossRefPubMed

44.

Han MJ, Kim BY, Yoon SO, Chung AS (2003) Cell proliferation induced by reactive oxygen species is mediated via mitogen-activated protein kinase in Chinese hamster lung fibroblast (V79) cells. Mol Cells 15:94–101PubMed

45.

Sato M, Shegogue D, Gore EA, Smith EA, McDeermott PJ, Trojanowska M (2002) Role of p38 MAPK in transforming growth factor beta stimulation of collagen production by scleroderma and healthy dermal fibroblasts. J Invest Dermatol 118:704–711CrossRefPubMed

46.

Agthong S, Tomlinson DR (2002) Inhibition of p38 MAP kinase corrects biochemical and neurological deficits in experimental diabetic neuropathy. Ann NY Acad Sci 973:359–362CrossRefPubMed

Titel: Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy
Publikationsdatum: 01.07.2004
Erschienen in: Diabetologia / Ausgabe 7/2004
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-004-1437-0

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 7/2004

Simple non-invasive assessment of advanced glycation endproduct accumulation

Reply to Comment on: Hales CN, Ozanne SE (2003) For Debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure

EASD News Section July 2004

WY-14643 and 9-cis-retinoic acid induce IRS-2/PI 3-kinase signalling pathway and increase glucose transport in human skeletal muscle cells: differential effect in myotubes from healthy subjects and Type 2 diabetic patients

Mutation at position −132 in the islet amyloid polypeptide (IAPP) gene promoter enhances basal transcriptional activity through a new CRE-like binding site