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. We used conditional gene deletion of MR signaling in myeloid cells (MR(flox/flox) LysM(Cre) mice; MyMRKO) or podocytes (MR(flox/flox) Pod(Cre) mice; 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, wild-type (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%±5%), 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-α, 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.

Eplerenone

Glomerulosclerosis

Proinflammatory cytokine

10.1681/asn.2012111094

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Citations (61)

Effect of interleukin-10 treatment on crescentic glomerulonephritis in rats

Kidney International (1997)

Steven J. Chadban Greg H. Tesch Hui Y. Lan Robert C. Atkins David J. Nikolic‐Paterson

Nephritis

10.1038/ki.1997.248

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Citations (33)

Induction of MIF synthesis and secretion by tubular epithelial cells: A novel action of angiotensin II

Kidney International (2003)

EDWINA K RICE Greg H. Tesch Zemin Cao Mark E. Cooper Christine N. Metz

Proinflammatory cytokine

10.1046/j.1523-1755.2003.00875.x

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Citations (55)

Pharmacological inhibition of protease‐activated receptor‐2 reduces crescent formation in rat nephrotoxic serum nephritis

Clinical and Experimental Pharmacology and Physiology (2019)

Yingjie Han Lifang Tian Frank Ma Greg H. Tesch David A. Vesey

Summary Glomerular crescent formation is a hallmark of rapidly progressive forms of glomerulonephritis. Thrombosis and macrophage infiltration are features of crescent formation in human and experimental kidney disease. Protease‐activated receptor‐2 (PAR‐2) is a G‐protein coupled receptor that links coagulation and inflammation. This study investigated whether pharmacological inhibition of PAR‐2 can suppress glomerular crescent formation in rat nephrotoxic serum nephritis (NTN). Disease was induced in Wistar Kyoto rats by immunisation with sheep IgG followed by administration of sheep nephrotoxic serum. Rats (n = 8/group) received the PAR‐2 antagonist (GB88, 10 mg/kg/p.o.), vehicle or no treatment starting 3 days before nephrotoxic serum injection and continuing until day 14. Vehicle and untreated rats developed thrombosis and macrophage infiltration in the glomerular tuft and Bowman's space in conjunction with prominent crescent formation. Activation of JNK signalling and proliferation in parietal epithelial cells was associated with crescent formation. GB88 treatment significantly reduced crescent formation with a substantial reduction in glomerular thrombosis, reduced macrophage infiltration in Bowman's space, and reduced activation of parietal epithelial cells. However, GB88 did not protect against the development of proteinuria, renal function impairment, inflammation or tubular cell damage in the NTN model. In conclusion, PAR‐2 plays a specific role in glomerular crescent formation by promoting glomerular thrombosis, macrophage accumulation in Bowman's space and activation of parietal epithelial cells.

Nephrotoxicity

Nephritis

Infiltration (HVAC)

10.1111/1440-1681.13077

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Citations (12)

Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis

Cell Death and Disease (2016)

Xiao‐Ming Meng Shuang Wang Xiao-Ru Huang Chen Yang Jun Xiao

Myofibroblasts play a central role in renal fibrosis although the origin of these cells remains controversial. We recently reported that bone marrow-derived macrophages can give rise to myofibroblasts through macrophage to myofibroblast transition (MMT). However, several important issues remain to be addressed, including whether MMT occurs in human kidney disease and verification of the MMT process through lineage tracing. Biopsies from a cohort of 58 patients with various forms of kidney disease were examined for MMT cells that co-express macrophage (CD68) and myofibroblast (α-smooth muscle actin, α-SMA) markers. MMT cells were evident in active fibrotic lesions, but were largely absent in acute inflammatory or sclerotic lesions, suggesting that MMT cells contribute to progressive renal fibrosis. Fate-mapping studies in LysMCreTomato mice identified substantial numbers of Tomato+ myeloid cells with F4/80+ macrophage phenotype expressing α-SMA and collagen I in the unilateral ureteral obstructive model of renal fibrosis, providing direct evidence for the MMT process during the development of renal fibrosis. In addition, MMT cells had a predominant M2 phenotype in both human and mouse renal fibrosis. Finally, selective depletion of myeloid cells via diphtheria toxin in LysMCreiDTR mice largely abolished macrophage infiltration and MMT cells in the obstructed kidney and substantially reduced accumulation of α-SMA+ myofibroblasts and collagen deposition, revealing a pathogenic role for inflammatory macrophages in MMT and tissue fibrosis. In conclusion, these findings provide substantial new data to support the postulate that macrophages can directly transdifferentiate into collagen-producing myofibroblasts in human and experimental kidney disease.

Myofibroblast

CD11c

CD68

10.1038/cddis.2016.402

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Citations (259)

262.3: Intragraft gene transcript changes with intravenous immunoglobulin therapy versus standard care in chronic antibody mediated rejection- vipar study cohort.

Transplantation (2024)

Dhakshayini Tharmaraj Greg H. Tesch Moshe Olshansky Kevan R. Polkinghorne Sukhpal Dayan

10.1097/01.tp.0001064968.64229.fa

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Citations (0)

A Novel, Small-Molecule Inhibitor of Ketohexokinase Attenuates Tubular Injury, Immune Cell Infiltration, and Renal Failure in Models of Acute and Chronic Kidney Injury

Journal of the American Society of Nephrology (2022)

Natalie Sroda Shawn S. Badal Ivan G. Gomez Maile Velasquez Y. Frank

Infiltration (HVAC)

Renal Injury

10.1681/asn.20223311s1597c

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Citations (0)

Proximal tubular epithelial cells preferentially endocytose covalently‐modified albumin compared to native albumin

Nephrology (2017)

Nguyen D K Ly Greg H. Tesch David J. Nikolic‐Paterson Philip Poronnik

ABSTRACT Aim Albumin can be covalently modified at surface lysine residues and thus the circulation contains a mixture of native albumin (i.e. not modified) and albumin with varying degrees of modification. Uptake and lysosomal degradation of glomerular filtered albumin by proximal tubular cells via the megalin scavenger receptor is considered an important mechanism to limit albumin loss in the urine. However, whether this is a general mechanism of tubular uptake of albumin or if this is restricted to modified albumin is unknown. To address this question, we investigated the uptake of modified versus native albumin by proximal tubular cells. Methods A well‐characterized proximal tubular cell model of albumin uptake was used to compare the uptake of modified albumin (covalent labelling of lysine residues with fluorescent probes) to that of native recombinant human albumin (rHA) labelled with 14 C during protein synthesis ( 14 C‐rHA). Results Opossum kidney (OK) cells showed significant uptake of fluorescence‐labelled albumin via an endocytosis mechanism. This uptake was inhibited by an equimolar ratio of different types of covalently modified albumin; however, purified bovine serum albumin and rHA failed to compete with the uptake of fluorescence‐labelled albumin. In contrast, OK cells failed to endocytose native 14 C‐rHA despite efficiently endocytosing covalently modified rHA. Conclusion Our studies show that OK cells preferentially endocytose covalently‐modified albumin compared to native albumin. This apparent selectivity of the megalin scavenger receptor complex suggests a specific role for this pathway in the removal of modified albumin from the circulation.

Scavenger Receptor

Serum Albumin

Bovine serum albumin

10.1111/nep.13211

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Citations (1)

The Role of p38α Mitogen-Activated Protein Kinase Activation in Renal Fibrosis

Journal of the American Society of Nephrology (2004)

Cosimo Stambe Robert C. Atkins Greg H. Tesch Masaki Takao George F. Schreiner

ABSTRACT. The p38 mitogen-activated protein kinase (MAPK) pathway transduces external stress stimuli and is important in extracellular matrix synthesis in cell types in vitro; however, its role in renal fibrosis is not known. Explored was the role the p38 MAPK pathway in rat unilateral ureteric obstruction (UUO), a model of renal fibrosis induced by a noninflammatory surgical insult. In a time-course study, a marked increase in phosphorylation (activation) of p38 in both interstitial myofibroblasts and tubules was shown. Rats were then treated daily with a specific inhibitor of p38α, NPC 31169, from the time of UUO surgery until being killed 7 d later. Compared with vehicle, NPC 31169–treated rats had a significant reduction in renal fibrosis assessed by interstitial volume, collagen IV deposition, and mRNA levels. This was primarily due to a reduction in the accumulation of interstitial myofibroblasts, as shown by a reduction in the area of immunostaining for alpha–smooth muscle actin and heat shock protein 47. The increase in renal TGF-β1 mRNA and protein levels in UUO was unaltered with NPC 31169 treatment; however, connective tissue growth factor mRNA was reduced. These results demonstrate that p38α MAPK plays an important role in renal fibrosis, acting downstream of TGF-β1. Blockade of p38 MAPK reduces extracellular matrix production and may be considered a potential therapeutic option in the treatment of renal fibrosis.

Myofibroblast

10.1097/01.asn.0000109669.23650.56

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Citations (195)