Lymphocytes promote albuminuria, but not renal dysfunction or histological damage in a mouse model of diabetic renal injury

Lim, Andy; Ma, Frank; Nikolic-Paterson, David J.; Kitching, A. Richard; Thomas, Merlin C.; Tesch, Gregory H

doi:10.1007/s00125-010-1757-1

Cited by 65 publications

(63 citation statements)

References 31 publications

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“…Indeed, there were no significant changes in other infiltrating immune cell types identified between diabetic mouse groups in the present study. This is consistent with a previous report from our group [23] suggesting that macrophages are the major immune cells contributing to renal functional changes and tubulo-interstitial fibrosis in experimental diabetes. There Cortical HMGB-1 (ng/mg protein) was evidence of reconstitution of glomerular cells by bone marrow from both donor groups as has been previously shown in diabetes [24], but the relative contribution of these remains to be delineated in future studies.…”

Section: Discussionsupporting

confidence: 94%

Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes

et al. 2014

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Aims/hypothesis The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bonemarrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. Methods Groups (n=8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT→WT) or RAGE-deficient (RG) mice (RG→WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks.Results Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-β were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG→WT mice also contained fewer infiltrating CD68 + macrophages that were activated. Diabetic RG→WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT → WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility Diabetologia (2014) 57:1977-1985 DOI 10.1007 box protein B-1 (HMGB-1) were also decreased in diabetic RG→WT compared with diabetic WT→WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. Conclusions/interpretation These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.

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Section: Discussionsupporting

confidence: 94%

Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes

et al. 2014

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“…8,[10][11][12]32 Animal model studies have demonstrated that glomerular levels of IgG increase with the duration of diabetes and correlate with albuminuria and renal inflammatory infiltrate. [33][34][35] Our study reveals glomerular immune deposits and high levels of total and oxidized LDL-specific antibodies in diabetic hypercholesterolemic mice, without differences between apoE and gapoE mice. Further analysis of IgM/IgG and Th1/Th2 ratios did not substantiate changes in lymphocyte responses.…”

Section: Discussionmentioning

confidence: 67%

Fcγ Receptor Deficiency Attenuates Diabetic Nephropathy

López-Parra

Mallavia

López-Franco

et al. 2012

Journal of the American Society of Nephrology

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Among patients with diabetes, increased production of immunoglobulins against proteins modified by diabetes is associated with proteinuria and cardiovascular risk, suggesting that immune mechanisms may contribute to the development of diabetes complications, such as nephropathy. We investigated the contribution of IgG Fcg receptors to diabetic renal injury in hyperglycemic, hypercholesterolemic mice. We used streptozotocin to induce diabetes in apolipoprotein E-deficient mice and in mice deficient in both apolipoprotein E and g-chain, the common subunit of activating Fcg receptors. After 15 weeks, the mice lacking Fcg receptors had significantly less albuminuria and renal hypertrophy, despite similar degrees of hyperglycemia and hypercholesterolemia, immunoglobulin production, and glomerular immune deposits. Moreover, diabetic Fcg receptor-deficient mice had less mesangial matrix expansion, inflammatory cell infiltration, and collagen and a-smooth muscle actin content in their kidneys. Accordingly, expression of genes involved in leukocyte infiltration, fibrosis, and oxidative stress was significantly reduced in diabetic kidneys and in mesangial cells cultured from Fcg receptor-deficient mice. In summary, preventing the activation of Fcg receptors alleviates renal hypertrophy, inflammation, and fibrosis in hypercholesterolemic mice with diabetes, suggesting that modulating Fcg receptor signaling may be renoprotective in diabetic nephropathy.

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“…Real-time PCR analysis was performed as previously described. 28 The Taqman probe and primer sequences are listed in Supplemental Table 3. Figure 7.…”

Section: Real-time Pcrmentioning

confidence: 99%

“…26 Immunoperoxidase staining for leukocytes (CD68, CD3, Ly6g) was performed on 2% paraformaldehydelysine-periodate-fixed kidney cryostat sections and assessed using established protocols. 28 Immunoperoxidase staining for MR, a-smooth muscle actin, activated caspase-3, and Wilms' tumor-1 was performed on formalin-fixed sections (4 mm) and analyzed according to a previous report. 28 All scoring was performed on blinded slides.…”

Section: Histology and Immunostainingmentioning

confidence: 99%

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Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

Huang

Nikolic-Paterson

Han

et al. 2014

Journal of the American Society of Nephrology

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Clinical and experimental studies have shown that mineralocorticoid receptor (MR) antagonists substantially reduce kidney injury. However, the specific cellular targets and mechanisms by which MR antagonists protect against kidney injury must be identified. PodMRKO) to establish the role of MR in these cell types in the development of mouse GN. Accelerated anti-glomerular basement membrane GN was examined in groups of mice: MyMRKO, PodMRKO, wildtype (WT) littermates, and WT mice receiving eplerenone (100 mg/kg twice a day; EPL-treated). At day 15 of disease, WT mice had glomerular crescents (37%65%), severe proteinuria, and a 6-fold increase in serum cystatin-C. MyMRKO, PodMRKO, and EPL-treated mice with GN displayed proteinuria similar to that in these disease controls. However, MyMRKO and EPL-treated groups had a 35% reduction in serum cystatin-C levels and reduced crescent numbers compared with WT mice, whereas PodMRKO mice were not protected. The protection observed in MyMRKO mice appeared to result predominantly from reduced recruitment of macrophages and neutrophils into the inflamed kidney. Suppression of kidney leukocyte accumulation in MyMRKO mice correlated with reductions in gene expression of proinflammatory molecules (TNF-a, inducible nitric oxide synthase, chemokine (C-C motif) ligand 2, matrix metalloproteinase-12), tubular damage, and renal fibrosis and was similar in EPL-treated mice. In conclusion, MR signaling in myeloid cells, but not podocytes, contributes to the progression of renal injury in mouse GN, and myeloid deficiency of MR provides protection similar to eplerenone in this disease.

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Lymphocytes promote albuminuria, but not renal dysfunction or histological damage in a mouse model of diabetic renal injury

Cited by 65 publications

References 31 publications

Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes

Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes

Fcγ Receptor Deficiency Attenuates Diabetic Nephropathy

Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

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