Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1

Mineralocorticoids stimulate renal tubular Na⁺ reabsorption, enhance salt appetite, increase blood pressure, and favor the development of renal fibrosis. The effects of mineralocorticoids on renal tubular Na⁺ reabsorption and salt appetite involve the serum- and glucocorticoid-inducible kinase 1 (SGK1). The kinase is highly expressed in fibrosing tissue. The present experiments thus explored the involvement of SGK1 in renal fibrosis. To this end, SGK1-knockout mice (sgk1 ^−/−) and their wild-type littermates (sgk1 ^+/+) were implanted with desoxycorticosterone acetate (DOCA)-release pellets and offered 1% saline as drinking water for 12 weeks. The treatment led to significant increases in fluid and Na⁺ intake and urinary output of fluid and Na⁺ in sgk1 ^+/+ mice, effects blunted in sgk1 ^−/− mice. Blood pressure increased within the first 7 weeks to a similar extent in both genotypes, but within the next 5 weeks, it increased further only in sgk1 ^+/+ mice. Creatinine clearance did not change significantly but albuminuria increased dramatically in sgk1 ^+/+ mice, an effect significantly blunted in sgk1 ^−/− mice. Histology after 12 weeks treatment revealed marked glomerular sclerosis and tubulointerstitial damage with interstitial fibrosis and inflammation in kidneys from sgk1 ^+/+ mice, but not from sgk1 ^−/− mice. In conclusion, a lack of SGK1 protects against DOCA/high-salt-induced albuminuria and renal fibrosis.     

Stimulation of electrogenic intestinal dipeptide transport by the glucocorticoid dexamethasone

According to recent in vitro experiments, the peptide transporter PepT2 is stimulated by the serum- and glucocorticoid-inducible kinase SGK1. The present study explored the contribution of SGK1 to the regulation of electrogenic intestinal peptide transport. Intestinal PepT1 was expressed in Xenopus oocytes, and peptide transport was determined by dual electrode voltage clamping. Peptide transport in intestinal segments was determined utilizing Ussing chamber. Cytosolic pH (pH _i ) was determined by BCECF fluorescence and Na⁺/H⁺ exchanger activity was estimated from Na⁺-dependent pH recovery (?pH _i ) following an ammonium pulse. In PepT1-expressing Xenopus oocytes, coexpression of SGK1 enhanced electrogenic peptide transport. Intestinal transport and pH _i of untreated mice were similar in SGK1 knockout mice (sgk1 ^?/? ) and their wild-type littermates (sgk1 ^+/+ ). Glucocorticoid treatment (4 days 10 µg/g body weight (bw)/day dexamethasone) increased peptide transport in sgk1 ^+/+ but not in sgk1 ^?/? mice. Irrespective of dexamethasone treatment, luminal peptide (5 mM glycyl-glycine) led to a similar early decrease of pH _i in sgk1 ^?/? and sgk1 ^+/+ mice, but to a more profound and sustained decline of pH _i in sgk1 ^?/? than in sgk1 ^+/+ mice. In the presence and absence of glycyl-glycine, ?pH _i was significantly enhanced by dexamethasone treatment in sgk1 ^+/+ mice, an effect significantly blunted in sgk1 ^?/? mice. During sustained exposure to glycyl-glycine, ?pH _i was significantly larger in sgk1 ^+/+ mice than in sgk1 ^?/? mice, irrespective of dexamethasone treatment. In conclusion, basal intestinal peptide transport does not require stimulation by SGK1. Glucocorticoid treatment stimulates both Na⁺/H⁺ exchanger activity and peptide transport, effects partially dependent on SGK1. Moreover, chronic exposure to glycyl-glycine stimulates Na⁺/H⁺ exchanger activity, an effect again involving SGK1.     

Decreased intestinal glucose transport in the sgk3-knockout mouse

Xenopus oocyte coexpression experiments revealed the capacity of the serum- and glucocorticoid-inducible kinase isoform 3 (SGK3) to up-regulate a variety of transport systems including the sodium-dependent glucose transporter SGLT1. The present study explored the functional significance of SGK3-dependent regulation of intestinal transport. To this end, experiments were performed in gene targeted mice lacking functional sgk3 (sgk3^–/–) and their wild type littermates (sgk3^+/+). Oral food intake and fecal dry weight were significantly larger in sgk3^–/– than in sgk3^+/+ mice. Glucose-induced current (I_g) in Ussing chamber as a measure of Na⁺ coupled glucose transport was significantly smaller in sgk3^–/– than in sgk3^+/+ mouse jejunal segments. Fasting plasma glucose concentrations were significantly lower in sgk3^–/– than in sgk3^+/+ mice. Intestinal electrogenic transport of phenylalanine, cysteine, glutamine and proline were not significantly different between sgk3^–/– and sgk3^+/+ mice. In conclusion, SGK3 is required for adequate intestinal Na⁺ coupled glucose transport and impaired glucose absorption may contribute to delayed growth and decreased plasma glucose concentrations of SGK3 deficient mice. The hypoglycemia might lead to enhanced food intake to compensate for impaired intestinal absorption.Ciprian Sandu, Rexhep Rexhepaj Shared first authorship.     

SGK1 is not required for regulation of colonic ENaC activity

The serum and glucocorticoid-inducible kinase SGK1 is known to be upregulated by mineralocorticoids and to enhance ENaC activity in several expression systems. Moreover, the amiloride-sensitive transepithelial potential difference in the collecting duct is lower in gene-targeted mice lacking SGK1 (sgk1 ^−/−) than in their wild-type littermates (sgk1 ^+/+). Accordingly, the ability of sgk1 ^−/− mice to decrease urinary sodium output during salt depletion is impaired. These observations highlight the importance of SGK1 in the stimulation of renal ENaC activity. In colonic epithelium, ENaC activity and, thus, transepithelial potential difference (V _te) are similarly upregulated by mineralocorticoids. The present study thus explored V _te and the apparent amiloride-sensitive equivalent short circuit current (I _amil) in the colon from sgk1 ^−/− and sgk1 ^+/+ mice before and after treatment with low salt diet, the glucocorticoid dexamethasone [DEXA, 10 μg/g body weight (BW)], or the mineralocorticoid deoxycorticosterone acetate (DOCA, 1.5 mg/day). Surprisingly, V _te and I _amil were both significantly (p<0.05) higher in sgk1 ^−/− than in sgk1 ^+/+ untreated mice. A 7-day exposure to low salt diet increased V _te and I _amil in both genotypes, but did not abrogate the differences of V _te and I _amil between sgk1 ^−/− and sgk1 ^+/+ mice. Plasma aldosterone levels were significantly higher in sgk1 ^−/− than in sgk1 ^+/+ mice both under control conditions and under low salt diet, which may explain the enhanced V _te in sgk1 ^−/− mice. Treatment with DEXA or DOCA both significantly increased V _te and I _amil in sgk1 ^+/+ mice and tended to increase V _te and I _amil in sgk1 ^−/− mice. Under treatment with DEXA or DOCA, V _te and I _amil were similar in sgk1 ^−/− and sgk1 ^+/+ mice. Fecal Na⁺ excretion was similar in sgk1 ^+/+ mice and in sgk1 ^−/− mice and was similarly decreased by low Na⁺ diet in both genotypes. In conclusion, transepithelial potential and amiloride-sensitive short circuit current are enhanced in the colonic epithelium of SGK1-deficient mice. Thus, lack of SGK1 does not disrupt colonic ENaC activity and its regulation by salt depletion.This article has a shared first authorship between Rexhep Rexhepaj and Ferruh Artunc.     

SGK1 dependence of insulin induced hypokalemia

Insulin stimulates cellular K⁺ uptake leading to hypokalemia. Cellular K⁺ uptake is accomplished by parallel stimulation of Na⁺/H⁺ exchange, Na⁺,K⁺,2Cl⁻ co-transport, and Na⁺/K⁺ ATPase and leads to cell swelling, a prerequisite for several metabolic effects of the hormone. Little is known about underlying signaling. Insulin is known to activate the serum and glucocorticoid-inducible kinase SGK1, which in turn enhances the activity of all three transport proteins. The present study thus explored the contribution of SGK1 to insulin-induced hypokalemia. To this end, gene-targeted mice lacking SGK1 (sgk1 ^−/− ) and their wild-type littermates (sgk1 ^+/+ ) have been infused with insulin (2 mU kg⁻¹ min⁻¹) and glucose at rates leaving the plasma glucose concentration constant. Moreover, isolated liver perfusion experiments have been performed to determine stimulation of cellular K⁺ uptake by insulin (100 nM). As a result, combined glucose and insulin infusion significantly decreased plasma K⁺ concentration despite a significant decrease of urinary K⁺ excretion in sgk1 ^+/+ but not in sgk1 ^−/− mice. Accordingly, the plasma K⁺ concentration was within 60 min significantly lower in sgk1 ^+/+ than in sgk1 ^−/− mice. In isolated liver perfusion experiments, cellular K⁺ uptake was stimulated by insulin (100 nM), an effect blunted by 72% in sgk1 ^−/− mice as compared to sgk1 ^+/+ mice. Accordingly, insulin-induced cell hydration was 63% lower in sgk1 ^−/− mice than in sgk1 ^+/+ mice. Moreover, volume regulatory K⁺ release was 31% smaller in sgk1 ^−/− mice than in sgk1 ^+/+ mice. In conclusion, the serum and glucocorticoid-inducible kinase SGK1 participates in the signaling mediating the hypokalemic effect of insulin.     

Renal Ca2+ handling in sgk1 knockout mice

Coexpression studies in Xenopus oocytes revealed the ability of the serum- and glucocorticoid-inducible kinase 1 (SGK1) to stimulate the renal epithelial Ca²⁺ channel TRPV5. SGK1 increases the abundance of the channel protein in the plasma membrane, an effect requiring the participation of the Na⁺/H⁺ exchanger regulating factor 2 (NHERF2). The present study was performed to explore the role of SGK1 in the regulation of renal Ca²⁺ handling in vivo. To this end, TRPV5, calbindin D-28K abundance, and renal Ca²⁺ excretion were analyzed in gene-targeted mice lacking functional SGK1 (sgk1 ^−/− ) and their age- and sex-matched littermates (sgk1 ^+/+ ). Immunohistochemistry revealed lower abundance of TRPV5 and calbindin D-28K protein in sgk1 ^−/− mice than in sgk1 ^+/+ mice, both fed with control diet. Feeding the mice a Ca²⁺-deficient diet marked ly increased TRPV5 protein abundance in both genotypes. Renal Ca²⁺ excretion under control diet was significantly lower in sgk1 ^−/− than in sgk1 ^+/+ mice. The Ca²⁺-deficient diet decreased renal excretion of Ca²⁺ to the same levels in both phenotypes. Furosemide increased fractional Ca²⁺ excretion and dissipated the difference between phenotypes. We conclude that lack of SGK1 may lead to decrease in TRPV5 abundance in connecting tubules but does not abrogate TRPV5 regulation. The decrease in abundance of TRPV5 in connecting tubules of sgk1 ^−/− mice is presumably compensated for by enhanced Ca²⁺ reabsorption in upstream nephron segments such as the loop of Henle, which may indirectly result from impaired SGK1-dependent Na⁺ reabsorption in the aldosterone-sensitive distal part of the nephron, salt loss, and enhanced Na⁺ (and Ca²⁺) reabsorption in those upstream nephron segments.D. Sandulace and F. Grahammer contributed equally to this work.     

Poly (ADP‐ribose) polymerase‐1 deficiency does not affect ethylnitrosourea mutagenicity in liver and testis of lacZ transgenic mice

Poly (ADP‐ribose) polymerase‐1 (Parp1) has been implicated in DNA base excision repair, single‐ and double‐strand break repair pathways, as well as in cell death by apoptosis or necrosis. We used Parp1^?/? lacZ plasmid‐based transgenic mice to investigate whether Parp1 deficiency influences the in vivo mutagenic and clastogenic response to the alkylating agent N‐ethyl‐N‐Nitrosourea (ENU) in somatic and germ‐cell tissues. The comparison of the lacZ mutant frequencies (MFs) between Parp1^+/+ and Parp1^?/? mice showed that the ablation of Parp1 does not affect the spontaneous or ENU‐induced MFs in liver and testis. In addition, the spectrum of the ENU‐induced mutations was not dependent on the Parp1 status, given that similar spectra, consisting mostly of point mutations and a small fraction of deletions/insertions, wereobserved in organs of both Parp1^?/? and Parp1^+/+ mice. Sequencing of point mutations revealed a consistent significant increase in A:T → T:A base substitutions, typically induced by ENU. Overall, we observed that neither the frequency nor the spectrum of ENU‐induced mutations demonstrated a specificity that could be attributed to the Parp1 impairment in mice organs. The analysis of micronucleus frequency in peripheral blood reticulocytes showed that ENU was clastogenic in both Parp1^?/? and Parp1^+/+ mice and had a strong cytotoxic effect in Parp1^?/? mice only. The present data suggest that, at a whole‐organism level, Parp1‐independent repair mechanisms may be operative in the removal of ENU‐induced DNA lesions or that highly damaged cells may be preferentially committed to death when Parp1 is inactivated. Environ. Mol. Mutagen. 2010. © 2010 Wiley‐Liss, Inc.     

Antigenotoxic effects of p53 on spontaneous and ultraviolet light B–induced deletions in the epidermis of gpt delta transgenic mice

Tumor development in the skin may be a multistep process where multiple genetic alterations occur successively. The p53 gene is involved in genome stability and thus is referred to as “the guardian of the genome.” To better understand the antigenotoxic effects of p53 in ultraviolet light B (UVB)‐induced mutagenesis, mutations were measured in the epidermis of UVB‐irradiated p53^+/+ and p53^?/? gpt delta mice. In the mouse model, point mutations and deletions are separately identified by the gpt and Spi^? assays, respectively. The mice were exposed to UVB at single doses of 0.5, 1.0, or 2.0 kJ/m². The mutant frequencies (MFs) were determined 4 weeks after the irradiation. All doses of UVB irradiation enhanced gpt MFs by about 10 times than that of unirradiated mice. There were no significant differences in gpt MFs and the mutation spectra between p53^+/+ and p53^?/? mice. The predominant mutations induced by UVB irradiation were G:C to A:T transitions at dipyrimidines. In contrast, in unirradiated p53^?/? mice, the frequencies of Spi^? large deletions of more than 1 kb and complex‐type deletions with rearrangements were significantly higher than those of the Spi^? large deletions in p53^+/+ counterparts. The specific Spi^? mutation frequency of more than 1 kb deletions and complex types increased in a dose‐dependent manner in the p53^+/+ mice. However, no increase of such large deletions was observed in irradiated p53^?/? mice. These results suggest that the antigenotoxic effects of p53 may be specific to deletions and complex‐type mutations induced by double‐strand breaks in DNA. Environ. Mol. Mutagen., 2011. © 2010 Wiley‐Liss, Inc.     

PKCη deficiency improves lipid metabolism and atherosclerosis in apolipoprotein E‐deficient mice

Genomewide association studies have shown that a nonsynonymous single nucleotide polymorphism in PRKCH is associated with cerebral infarction and atherosclerosis‐related complications. We examined the role of PKCη in lipid metabolism and atherosclerosis using apolipoprotein E‐deficient (Apoe^?/?) mice. PKCη expression was augmented in the aortas of mice with atherosclerosis and exclusively detected in MOMA2‐positive macrophages within atherosclerotic lesions. Prkch^+/+Apoe^?/? and Prkch^?/?Apoe^?/? mice were fed a high‐fat diet (HFD), and the dyslipidemia observed in Prkch^+/+Apoe^?/? mice was improved in Prkch^?/?Apoe^?/? mice, with a particular reduction in serum LDL cholesterol and phospholipids. Liver steatosis, which developed in Prkch^+/+Apoe^?/? mice, was improved in Prkch^?/?Apoe^?/? mice, but glucose tolerance, adipose tissue and body weight, and blood pressure were unchanged. Consistent with improvements in LDL cholesterol, atherosclerotic lesions were decreased in HFD‐fed Prkch^?/?Apoe^?/? mice. Immunoreactivity against 3‐nitrotyrosine in atherosclerotic lesions was dramatically decreased in Prkch^?/?Apoe^?/? mice, accompanied by decreased necrosis and apoptosis in the lesions. ARG2 mRNA and protein levels were significantly increased in Prkch^?/?Apoe^?/? macrophages. These data show that PKCη deficiency improves dyslipidemia and reduces susceptibility to atherosclerosis in Apoe^?/? mice, showing that PKCη plays a role in atherosclerosis development.     

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

The T‐cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4⁺ T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4⁺ T‐cell‐mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6^?/? mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3⁺ cell frequency characterized CNS tissues from CCR6^?/? compared with CCR6^+/+ mice during the disease effector phase. Transfer of CCR6^+/+ Treg to CCR6^?/? mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3⁺ cells and recovery of the cytokine balance in CCR6^?/? mouse CNS. Competitive assays between CCR6^+/+ and CCR6^?/? Treg adoptively transferred to CCR6^?/? mice showed impaired ability of CCR6^?/? Treg to infiltrate CNS tissues in EAE‐affected mice. Our data indicate a CCR6 requirement by CD4⁺ Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE.     

NTPDase1 governs P2X7‐dependent functions in murine macrophages

P2X₇ receptor is an adenosine triphosphate (ATP)‐gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X₇ effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X₇‐dependent responses in these cells. Macrophages isolated from NTPDase1‐null mice (Entpd1^?/?) were devoid of all ADPase and most ATPase activities when compared with WT macrophages (Entpd1^+/+). Entpd1^?/? macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL‐1β and IL‐18 after TLR2 or TLR4 priming, and incorporated the fluorescent dye Yo‐Pro‐1 more efficiently (suggestive of increased pore formation) than Entpd1^+/+ cells. Consistent with these observations, NTPDase1 regulated P2X₇‐associated IL‐1β release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase‐1. NTPDase1 also inhibited IL‐1β release in vivo in the air pouch inflammatory model. Exudates of LPS‐injected Entpd1^?/? mice had significantly higher IL‐1β levels when compared with Entpd1^+/+ mice. Altogether, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X₇‐dependent macrophage responses.     

IL-10 contributes to the suppressive function of tumour-associated myeloid cells and enhances myeloid cell accumulation in tumours

Studies have revealed that tumour‐associated myeloid cells (TAMC) are one of the major sources of IL‐10 in tumour‐bearing mice. However, the significance of TAMC‐derived IL‐10 in tumour immunity is poorly understood. Here, we show that IL‐10 blockade or IL‐10 deficiency reduces the capacity of TAMC in suppressing the proliferation of P1A‐specific CD8 T cells. In the spleen, IL‐10‐deficient and wild‐type (WT) mice bearing large tumour burdens have similar TAMC populations. The tumours from IL‐10‐deficient mice, however, have reduced numbers of TAMC compared with tumours from their WT counterparts. IL‐10^?/?RAG‐2^?/? mice also had reduced numbers of TAMC compared with tumours from IL‐10^+/+RAG‐2^?/? mice; therefore, the reduction in TAMC in IL‐10‐deficient tumours was not because of adaptive immune response in tumours. Adoptively transferred tumour antigen–specific CD8 T cells expanded more efficiently within tumours in IL‐10^?/?RAG‐2^?/? mice than in tumours from IL‐10^+/+RAG‐2^?/? mice. Cytotoxic T lymphocyte adoptive transfer therapy prevented tumour evasion in IL‐10^?/?RAG‐2^?/? mice more efficiently than in IL‐10^+/+RAG‐2^?/? mice. Thus, IL‐10 enhances the accumulation of myeloid cells in tumours, and TAMC‐derived IL‐10 suppresses the activation and expansion of tumour antigen–specific T cells.     

Parp‐1 deficiency in ES cells promotes invasive and metastatic lesions accompanying induction of trophoblast giant cells during tumorigenesis in uterine environment

Embryonic stem (ES) cells deficient in poly(ADP‐ribose) polymerase‐1 (Parp‐1) develop into teratocarcinomas with the appearance of trophoblast giant cells (TGCs) when injected subcutaneously into nude mice. Because the uterus is one of the original organs in which germ cell tumors develop with induction of trophoblast lineage, here we investigated whether Parp‐1 deficiency in ES cells affects teratocarcinoma formation processes by grafting ES cells into the horns of uteri. Teratocarcinomas developed from both wild‐type (Parp‐1^+/+) and Parp‐1^?/? ES cells. The weights of the tumors derived from Parp‐1^?/? ES cells were lower than those of the tumors derived from Parp‐1^+/+ ES cells (P < 0.05). The Parp‐1^?/? tumors showed the appearance of TGCs. Notably, organ metastasis to the lung and liver was observed for the Parp‐1^?/? tumors, but not for the Parp‐1^+/+ tumors (P < 0.05). Invasions were more frequently observed with the Parp‐1^?/? tumors compared with the Parp‐1^+/+ tumors (P < 0.05). Since TGCs are known to have invasive properties, the appearance of TGCs may have supported the metastatic process. The present findings suggest that loss of Parp‐1 during teratocarcinoma formation might augment invasive and metastatic properties of the tumors in the uterine environment.     

SGK1 activity in Na+ absorbing airway epithelial cells monitored by assaying NDRG1-Thr346/356/366 phosphorylation

Studies of HeLa cells and serum- and glucocorticoid-regulated kinase 1 (SGK1) knockout mice identified threonine residues in the n-myc downstream-regulated gene 1 protein (NDRG1-Thr^346/356/366) that are phosphorylated by SGK1 but not by related kinases (Murray et al., Biochem J 385:1–12, 2005). We have, therefore, monitored the phosphorylation of NDRG1-Thr^346/356/366 in order to explore the changes in SGK1 activity associated with the induction and regulation of the glucocorticoid-dependent Na⁺ conductance (G _Na) in human airway epithelial cells. Transient expression of active (SGK1-S422D) and inactive (SGK1-K127A) SGK1 mutants confirmed that activating SGK1 stimulates NDRG1-Thr^346/356/366 phosphorylation. Although G _Na is negligible in hormone-deprived cells, these cells displayed basal SGK1 activity that was sensitive to LY294002, an inhibitor of 3-phosphatidylinositol phosphate kinase (PI3K). Dexamethasone (0.2 μM) acutely activated SGK1 and the peak of this response (2–3 h) coincided with the induction of G _Na, and both responses were PI3K-dependent. While these data suggest that SGK1 might mediate the rise in G _Na, transient expression of the inactive SGK1-K127A mutant did not affect the hormonal induction of G _Na but did suppress the activation of SGK1. Dexamethasone-treated cells grown on permeable supports formed confluent epithelial sheets that generated short circuit current due to electrogenic Na⁺ absorption. Forskolin and insulin both stimulated this current and the response to insulin, but not forskolin, was LY294002-sensitive and associated with the activation of SGK1. While these data suggest that SGK1 is involved in the control of G _Na, its role may be minor, which could explain why sgk1 knockout has different effects upon different tissues.     

Under‐expression of α8 integrin aggravates experimental atherosclerosis

Integrins play an important role in vascular biology. The α8 integrin chain attenuates smooth muscle cell migration but its functional role in the development of atherosclerosis is unclear. Therefore, we studied the contribution of α8 integrin to atherosclerosis and vascular remodelling. We hypothesized that α8 integrin expression is reduced in atherosclerotic lesions, and that its under‐expression leads to a more severe course of atherosclerosis. α8 Integrin was detected by immunohistochemistry and qPCR and α8 integrin‐deficient mice were used to induce two models of atherosclerotic lesions. First, ligation of the carotid artery led to medial thickening and neointima formation, which was quantified in carotid cross‐sections. Second, after crossing into ApoE‐deficient mice, the formation of advanced vascular lesions with atherosclerotic plaques was quantified in aortic en face preparations stained with Sudan IV. Parameters of renal physiology and histopathology were assessed: α8 integrin was detected in the media of human and murine vascular tissue and was down‐regulated in arteries with advanced atherosclerotic lesions. In α8 integrin‐deficient mice (α8^?/?) as well as α8^+/? and α8^+/+ littermates, carotid artery ligation increased media:lumen ratios in all genotypes, with higher values in ligated α8^?/? and α8^+/? compared to ligated α8^+/+ animals. Carotid artery ligation increased smooth muscle cell number in the media of α8^+/+ mice and, more prominently, of α8^?/? or α8^+/? mice. On an ApoE^?/? background, α8^+/? and α8^?/? mice developed more atherosclerotic plaques than α8^+/+ mice. α8 Integrin expression was reduced in α8^+/? animals. Renal damage with increased serum creatinine and glomerulosclerosis was detected in α8^?/? mice only. Thus, under‐expression of α8 integrin aggravates vascular lesions, while a complete loss of α8 integrin results in reduced renal mass and additional renal disease in the presence of generalized atherosclerosis. Our data support the hypothesis that integrin α8β1 has a protective role in arterial remodelling and atherosclerosis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.