The growth factor midkine regulates the renin-angiotensin system in mice
Open Access
- 1 June 2009
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 119 (6), 1616-1625
- https://doi.org/10.1172/jci37249
Abstract
The renin-angiotensin system plays a pivotal role in regulating blood pressure and is involved in the pathogenesis of kidney disorders and other diseases. Here, we report that the growth factor midkine is what we believe to be a novel regulator of the renin-angiotensin system. The hypertension induced in mice by 5/6 nephrectomy was accompanied by renal damage and elevated plasma angiotensin II levels and was ameliorated by an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker. Notably, ACE activity in the lung, midkine expression in the lung, and midkine levels in the plasma were all increased after 5/6 nephrectomy. Exposure to midkine protein enhanced ACE expression in primary cultured human lung microvascular endothelial cells. Furthermore, hypertension was not induced and renal damage was less severe in midkine-deficient mice. Supplemental administration of midkine protein to midkine-deficient mice restored ACE expression in the lung and hypertension after 5/6 nephrectomy. Oxidative stress might be involved in midkine expression, since expression of NADH/NADPH oxidase–1, –2, and –4 was induced in the lung after 5/6 nephrectomy. Indeed, the antioxidative reagent tempol reduced midkine expression and plasma angiotensin II levels and consequently ameliorated hypertension. These results suggest that midkine regulates the renin-angiotensin system and mediates the kidney-lung interaction after 5/6 nephrectomy.Keywords
This publication has 63 references indexed in Scilit:
- Role of Inflammation in the Development of Renal Damage and Dysfunction in Angiotensin II–Induced HypertensionHypertension, 2008
- Therapeutic strategies to slow chronic kidney disease progressionPediatric Nephrology, 2008
- Anti-inflammatory Renoprotective Effect of Clopidogrel and Irbesartan in Chronic Renal InjuryJournal of the American Society of Nephrology, 2008
- Purinergic receptors contribute to early mesangial cell transformation and renal vessel hypertrophy during angiotensin II-induced hypertensionAmerican Journal of Physiology-Renal Physiology, 2008
- The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney DiseasePharmacological Reviews, 2007
- Mechanisms of Disease: oxidative stress and inflammation in the pathogenesis of hypertensionNature Clinical Practice Nephrology, 2006
- Midkine, a newly discovered regulator of the renin–angiotensin pathway in mouse aorta: Significance of the pleiotrophin/midkine developmental gene family in angiotensin II signalingBiochemical and Biophysical Research Communications, 2005
- Midkine, a heparin-binding cytokine, plays key roles in intraperitoneal adhesionsBiochemical and Biophysical Research Communications, 2004
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Purification of recombinant midkine and examination of its biological activities: Functional comparison of new heparin binding factorsBiochemical and Biophysical Research Communications, 1991