Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (GN). To date, treatment of most patients with ANCA-GN relies on non-specific immunosuppressive agents, which may have serious adverse effects and be only partially effective. Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4+ and CD8+ T cells as a pathogenic signature. We then utilize these transcriptomic profiles for digital pharmacology and identify ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, as the strongest therapeutic drug to use. Moreover, four patients with relapsing ANCA-GN are treated with ustekinumab in combination with low-dose cyclophosphamide and steroids, with ustekinumab given subcutaneously (90 mg) at weeks 0, 4, 12, and 24. Patients are followed up for 26 weeks to find this treatment well-tolerated and inducing clinical responses, including improved kidney function and Birmingham Vasculitis Activity Score, in all ANCA-GN patients. Our findings thus suggest that targeting of pathogenic T cells in ANCA-GN patients with ustekinumab might represent a potential approach and warrants further investigation in clinical trials.

Role of the Anaphylatoxin Receptor C5aR2 in Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage.

BACKROUND: Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1-/- mice have reduced hypertensive renal injury. The role of C5aR2 in hypertension is unknown. METHODS: For examination of C5aR2 expression on infiltrating and resident renal cells a tandem dye Tomato-C5aR2 knock-in reporter mouse was used. Human C5aR2 expression was analyzed in a single-cell RNAseq data set from the kidneys of hypertensive patients. Finally, we examined the effect of angiotensin II-induced hypertension in C5aR2-deficient mice. RESULTS: Flow cytometric analysis of leukocytes isolated from kidneys of the reporter mice showed that dendritic cells are the major C5aR2-expressing population (34%) followed by monocyte/macrophages (30%) and neutrophils (14%). Using confocal microscopy C5aR2 was not detected in resident renal or cardiac cells. In the human kidney, C5aR2 was also mainly found in monocytes, macrophages, and dendritic cells with a significantly higher expression in hypertension (P < 0.05). Unilateral nephrectomy was performed followed by infusion of Ang II (0.75 ng/g/min) and a high salt diet in wildtype (n = 18) and C5aR2-deficient mice (n = 14). Blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation), and cardiac injury (cardiac fibrosis, heart weight, gene expression) did not differ between hypertensive wildtype and C5aR2-/- mice. CONCLUSIONS: In summary, C5aR2 is mainly expressed in myeloid cells in the kidney in mice and humans but its deficiency has no effect on Ang II-induced hypertensive injury.

Deficiency of Complement C3a and C5a receptors Does Not Prevent Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage.

BACKGROUND: Complement may drive the pathology of hypertension through effects on innate and adaptive immune responses. Recently an injurious role for the anaphylatoxin receptors C3aR (complement component 3a receptor) and C5aR1 (complement component 5a receptor) in the development of hypertension was shown through downregulation of Foxp3+ (forkhead box protein 3) regulatory T cells. Here, we deepen our understanding of the therapeutic potential of targeting both receptors in hypertension. METHODS: Data from the European Renal cDNA Bank, single cell sequencing and immunohistochemistry were examined in hypertensive patients. The effect of C3aR or C3aR/C5aR1 double deficiency was assessed in two models of Ang II (angiotensin II)-induced hypertension in knockout mice. RESULTS: We found increased expression of C3aR, C5aR1 and Foxp3 cells in kidney biopsies of patients with hypertensive nephropathy. Expression of both receptors was mainly found in myeloid cells. No differences in blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation) or cardiac injury (cardiac fibrosis, heart weight, gene expression) between control and mutant mice was discerned in C3aR-/- as well as C3aR/C5aR1-/- double knockout mice. The number of renal Tregs was not decreased in Ang II as well as in DOCA salt induced hypertension. CONCLUSIONS: Hypertensive nephropathy in mice and men is characterized by an increase of renal regulatory T cells and enhanced expression of anaphylatoxin receptors. Our investigations do not corroborate a role for C3aR/C5aR1 axis in Ang II-induced hypertension hence challenging the concept of anaphylatoxin receptor targeting in the treatment of hypertensive disease.

Increased blood pressure after nonsevere COVID-19.

BACKGROUND: Various sequelae have been described after nonsevere coronavirus disease 2019 (COVID-19), but knowledge on postacute effects on blood pressure is limited. METHODS: This is a cross-sectional analysis of blood pressure profiles in individuals after nonsevere COVID-19 compared with matched population-based individuals without prior COVID-19. Data were derived from the ongoing and prospective Hamburg City Health Study, a population-based study in Hamburg, Germany, and its associated COVID-19 program, which included individuals at least 4 months after COVID-19. Matching was performed by age, sex, education, and preexisting hypertension in a 1 : 4 ratio. RESULTS: Four hundred and thirty-two individuals after COVID-19 (mean age 56.1 years) were matched to 1728 controls without prior COVID-19 (56.2 years). About 92.8% of COVID-19 courses were mild or moderate, only 7.2% were hospitalized, and no individual had been treated on an intensive care unit. Even after adjustment for relevant competing risk factors, DBP [+4.7 mmHg, 95% confidence interval (95% CI) 3.97-5.7, P  < 0.001] was significantly higher in individuals after COVID-19. For SBP, a trend towards increased values was observed (+1.4 mmHg, 95% CI -0.4 to 3.2, P  = 0.120). Hypertensive blood pressures at least 130/80 mmHg (according to the ACC/AHA guideline) and at least 140/90 mmHg (ESC/ESH guideline) occurred significantly more often in individuals after COVID-19 than matched controls (odds ratio 2.0, 95% CI 1.5-2.7, P  < 0.001 and odds ratio 1.6, 95% CI 1.3-2.0, P  < 0.001, respectively), mainly driven by changes in DBP. CONCLUSION: Blood pressure is higher in individuals after nonsevere COVID-19 compared with uninfected individuals suggesting a significant hypertensive sequela.

Complement component C3 as a new target to lower albuminuria in hypertensive kidney disease.

BACKGROUND AND PURPOSE: Complement activation may drive hypertension through its effects on immunity and tissue integrity. EXPERIMENTAL APPROACH: We examined expression of C3, the central protein of the complement cascade, in hypertension. KEY RESULTS: Increased C3 expression was found in kidney biopsies and micro-dissected glomeruli of patients with hypertensive nephropathy. Renal single cell RNA sequence data from normotensive and hypertensive patients confirmed expression of C3 in different cellular compartments of the kidney. In angiotensin II (Ang II) induced hypertension renal C3 expression was up-regulated. C3-/- mice revealed a significant lower albuminuria in the early phase of hypertension. However, no difference was found for blood pressure, renal injury (histology, glomerular filtration rate, inflammation) and cardiac injury (fibrosis, weight, gene expression) between C3-/- and wildtype mice after Ang II infusion. Also, in deoxycorticosterone acetate (DOCA) salt hypertension, a significantly lower albuminuria was found in the first weeks of hypertension in C3 deficient mice but no significant difference in renal and cardiac injury. Down-regulation of C3 by C3 targeting GalNAc (n-acetylgalactosamine) small interfering RNA (siRNA) conjugate decreased C3 in the liver by 96% and lowered albuminuria in the early phase but showed no effect on blood pressure and end-organ damage. Inhibition of complement C5 by siRNA showed no effect on albuminuria. CONCLUSION AND IMPLICATIONS: Increased C3 expression is found in the kidneys of hypertensive mice and men. Genetic and therapeutic knockdown of C3 improved albuminuria in the early phase of hypertension but did not ameliorate arterial blood pressure nor renal and cardiac injury.

Left ventricular myocardial strain responding to chronic pressure overload in patients with resistant hypertension evaluated by feature-tracking CMR.

OBJECTIVES: The study aimed to investigate the alterations of myocardial deformation responding to long-standing pressure overload and the effects of focal myocardial fibrosis using feature-tracking cardiac magnetic resonance (FT-CMR) in patients with resistant hypertension (RH). METHODS: Consecutive RH patients were prospectively recruited and underwent CMR at a single institution. FT-CMR analyses based on cine images were applied to measure left ventricular (LV) peak systolic global longitudinal (GLS), radial (GRS), and circumferential strain (GCS). Functional and morphological CMR variables, and late gadolinium enhancement (LGE) imaging were also obtained. RESULTS: A total of 50 RH patients (63 ± 12 years, 32 men) and 18 normotensive controls (57 ± 8 years, 12 men) were studied. RH patients had a higher average systolic blood pressure than controls (166 ± 21 mmHg vs. 116 ± 8 mmHg, p < 0.001) with the intake of 5 ± 1 antihypertensive drugs. RH patients showed increased LV mass index (78 ± 15 g/m2 vs. 61 ± 9 g/m2, p < 0.001), decreased GLS (- 16 ± 3% vs. - 19 ± 2%, p = 0.001) and GRS (41 ± 12% vs. 48 ± 8%, p = 0.037), and GCS was reduced by trend (- 17 ± 4% vs. - 19 ± 4%, p = 0.078). Twenty-one (42%) RH patients demonstrated a LV focal myocardial fibrosis (LGE +). LGE + RH patients had higher LV mass index (85 ± 14 g/m2 vs. 73 ± 15 g/m2, p = 0.007) and attenuated GRS (37 ± 12% vs. 44 ± 12%, p = 0.048) compared to LGE - RH patients, whereas GLS (p = 0.146) and GCS (p = 0.961) were similar. CONCLUSION: Attenuation of LV GLS and GRS, and GCS decline by tendency, might be adaptative changes responding to chronic pressure overload. There is a high incidence of focal myocardial fibrosis in RH patients, which is associated with reduced LV GRS. CLINICAL RELEVANCE STATEMENT: Feature-tracking CMR-derived myocardial strain offers insights into the influence of long-standing pressure overload and of a myocardial fibrotic process on cardiac deformation in patients with resistant hypertension. KEY POINTS: • Variations of left ventricular strain are attributable to the degree of myocardial impairment in resistant hypertensive patients. • Focal myocardial fibrosis of the left ventricle is associated with attenuated global radial strain. • Feature-tracking CMR provides additional information on the attenuation of myocardial deformation responding to long-standing high blood pressure.

CD4+ T cells produce GM-CSF and drive immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12.

GM-CSF in glomerulonephritisDespite glomerulonephritis being an immune-mediated disease, the contributions of individual immune cell types are not clear. To address this gap in knowledge, Paust et al. characterized pathological immune cells in samples from patients with glomerulonephritis and in samples from mice with the disease. The authors found that CD4+ T cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF) licensed monocytes to promote disease by producing matrix metalloproteinase 12 and disrupting the glomerular basement membrane. Targeting GM-CSF to inhibit this axis reduced disease severity in mice, implicating this cytokine as a potential therapeutic target for patients with glomerulonephritis. -CM.

Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury.

Glucocorticoids remain a cornerstone of therapeutic regimes for autoimmune and chronic inflammatory diseases - for example, in different forms of crescentic glomerulonephritis - because of their rapid antiinflammatory effects, low cost, and wide availability. Despite their routine use for decades, the underlying cellular mechanisms by which steroids exert their therapeutic effects need to be fully elucidated. Here, we demonstrate that high-dose steroid treatment rapidly reduced the number of proinflammatory CXCR3+CD4+ T cells in the kidney by combining high-dimensional single-cell and morphological analyses of kidney biopsies from patients with antineutrophil cytoplasmic antibody-associated (ANCA-associated) crescentic glomerulonephritis. Using an experimental model of crescentic glomerulonephritis, we show that the steroid-induced decrease in renal CD4+ T cells is a consequence of reduced T cell recruitment, which is associated with an ameliorated disease course. Mechanistic in vivo and in vitro studies revealed that steroids act directly on renal tissue cells, such as tubular epithelial cells, but not on T cells, which resulted in an abolished renal expression of CXCL9 and CXCL10 as well as in the prevention of CXCR3+CD4+ T cell recruitment to the inflamed kidneys. Thus, we identified the CXCL9/CXCL10-CXCR3 axis as a previously unrecognized cellular and molecular target of glucocorticoids providing protection from immune-mediated pathology.

Mosaic theory revised: inflammation and salt play central roles in arterial hypertension.

The mosaic theory of hypertension was advocated by Irvine Page ~80 years ago and suggested that hypertension resulted from the close interactions of different causes. Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by the proposed mechanisms that result in hemodynamic injury. Inflammation plays an important role in the pathophysiology and contributes to the deleterious consequences of arterial hypertension. Sodium intake is indispensable for normal body function but can be detrimental when it exceeds dietary requirements. Recent data show that sodium levels also modulate the function of monocytes/macrophages, dendritic cells, and different T-cell subsets. Some of these effects are mediated by changes in the microbiome and metabolome due to high-salt intake. The purpose of this review is to propose a revised and extended version of the mosaic theory by summarizing and integrating recent advances in salt, immunity, and hypertension research. Salt and inflammation are placed in the middle of the mosaic because both factors influence each of the remaining pieces.

The role of the mineralocorticoid receptor in immune cells in cardiovascular disease.

Chronic low-grade inflammation and immune cell activation are important mechanisms in the pathophysiology of cardiovascular disease (CVD). Therefore, targeted immunosuppression is a promising novel therapy to reduce cardiovascular risk. In this review, we identify the mineralocorticoid receptor (MR) on immune cells as a potential target to modulate inflammation. The MR is present in almost all cells of the cardiovascular system, including immune cells. Activation of the MRs in innate and adaptive immune cells induces inflammation which can contribute to CVD, by inducing endothelial dysfunction and hypertension. Moreover, it accelerates atherosclerotic plaque formation and destabilization and impairs tissue regeneration after ischaemic events. Identifying the molecular targets for these non-renal actions of the MR provides promising novel cardiovascular drug targets for mineralocorticoid receptor antagonists (MRAs), which are currently mainly applied in hypertension and heart failure. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.

Immune mechanisms in arterial hypertension. Recent advances.

Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by hemodynamic injury. Inflammation also plays an important role in the pathophysiology and contributes to the deleterious consequences of this disease. Cells of the innate immune system including monocyte/macrophages and dendritic cells can promote blood pressure elevation via effects mostly on kidney and vascular function. Moreover, convincing evidence shows that T and B cells from the adaptive immune system are involved in hypertension and hypertensive end-organ damage. Skin monocyte/macrophages, regulatory T cells, natural killer T cells, and myeloid-derived suppressor cells have been shown to exert blood pressure controlling effects. Sodium intake is undoubtedly indispensable for normal body function but can be detrimental when taken in excess of dietary requirements. Sodium levels also modulate the function of monocyte/macrophages, dendritic cells, and different T cell subsets. Some of these effects are mediated by changes in the microbiome and metabolome that can be found after high salt intake. Modulation of the immune response can reduce severity of blood pressure elevation and hypertensive end-organ damage in several animal models. The purpose of this review is to briefly summarize recent advances in immunity and hypertension as well as hypertensive end-organ damage.

The role of complement in arterial hypertension and hypertensive end organ damage.

Increasing evidence indicates that hypertension and hypertensive end organ damage are not only mediated by haemodynamic injury but that inflammation also plays an important role. The complement system protects the host from a hostile microbial environment and maintains tissue and cell integrity through the elimination of altered or dead cells. As an important effector arm of innate immunity, it plays also central roles in the regulation of adaptive immunity. Thus, complement activation may drive the pathology of hypertension through its effects on innate and adaptive immune responses, aside from direct effects on the vasculature. Recent experimental data strongly support a role for complement in all stages of arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical haemolytic uraemic syndrome suggest also a role for complement in the development of malignant nephrosclerosis. Here, we review the role of complement in hypertension and hypertensive end organ damage. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.

B6.Rag1 Knockout Mice Generated at the Jackson Laboratory in 2009 Show a Robust Wild-Type Hypertensive Phenotype in Response to Ang II (Angiotensin II).

A key finding supporting a causal role of the immune system in the pathogenesis of hypertension is the observation that RAG1 knockout mice on a C57Bl/6J background (B6.Rag1-/-), which lack functional B and T cells, develop a much milder hypertensive response to Ang II (angiotensin II) than control C57Bl/6J mice. Here, we report that we never observed any Ang II resistance of B6.Rag1-/- mice purchased directly from the Jackson Laboratory as early as 2009. B6.Rag1-/- mice displayed nearly identical blood pressure increases monitored via radiotelemetry and hypertensive end-organ damage in response to different doses of Ang II and different levels of salt intake (0.02%, 0.3%, and 3% NaCl diet). Similarly, restoration of T-cell immunity by adoptive cell transfer did not affect the blood pressure response to Ang II in B6.Rag1-/- mice. Full development of the hypertension-resistant phenotype in B6.Rag1-/- mice appears to depend on the action of yet unidentified nongenetic modifiers in addition to the absence of functional T cells.

Effect of renal denervation procedure on left ventricular mass, myocardial strain and diastolic function by CMR on a 12-month follow-up.

PURPOSE: To investigate the effects of renal denervation (RDN) on left ventricular (LV) mass, myocardial strain and diastolic function in patients with treatment-resistant arterial hypertension by cardiac magnet resonance imaging on a 12-month follow-up. MATERIALS AND METHODS: Sixteen patients (38% female) were examined before and 12 months after RDN. LV morphology and strain were analyzed. Diastolic function was determined by early (EPFR) and atrial peak filling rates (APFR) derived from differential volume-time-curve analysis. Clinical visits included 24-h ambulant blood pressure monitoring (ABPM). RESULTS: Twelve months after RDN LV mass decreased from 80 ± 21 g/m2 to 74 ± 20 g/m2 (P < 0.05). Global radial (35 ± 12% vs. 41 ± 10%, P < 0.05) and longitudinal strain improved (- 15 ± 4% vs. - 17 ± 3%, P < 0.05). Global circumferential strain (- 16 ± 5% vs. - 18 ± 4%, P = 0.12) remained unchanged. The parameter of diastolic LV function PFRR (EPFR/APFR) improved following RDN (0.9 ± 0.4 vs. 1.1 ± 0.5, P < 0.05). Individual changes of LV mass were associated with an increase of EPFR (r = - 0.54, P < 0.05) and a reduction of APFR by trend (r = 0.45, P = 0.08). Systolic ABPM showed a decrease by trend (152 mmHg vs. 148 mmHg, P = 0.08). CONCLUSIONS: After RDN we observed a reduction of LV mass, improvement of global strain and diastolic function.

Salt, inflammation, IL-17 and hypertension.

Traditionally, arterial hypertension and subsequent end-organ damage have been attributed to haemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign microorganisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Over the past few years, important findings have revolutionized hypertension research. Firstly, in 2007, a seminal paper showed that adaptive immunity is involved in the pathogenesis of hypertension. Secondly, salt storage in the skin and its consequences for cardiovascular physiology were discovered. Thirdly, after the discovery that salt promotes the differentiation of CD4+ T cells into TH 17 cells, it was demonstrated that salt directly changes several cells of the innate and adaptive immune system and aggravates autoimmune disease but may improve antimicrobial defence. Herein, we will review pathways of activation of immune cells by salt in hypertension as the framework for understanding the multiple roles of salt and immunity in arterial hypertension and autoimmune disease. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

Adaptive immunity and IL-17A are not involved in the progression of chronic kidney disease after 5/6 nephrectomy in mice.

BACKGROUND AND PURPOSE: The adaptive immune response and IL-17A contribute to renal damage in several experimental models of renal injury. EXPERIMENTAL APPROACH: To evaluate the role of the adaptive immune response, 5/6 nephrectomy was performed in wildtype DBA/1J mice and in recombination-activating gene-1 (RAG-1) deficient mice that lack B and T-cells. To assess the role of IL-17A, we carried out 5/6 nephrectomy in IL-17A deficient mice. Flow cytometric analysis, immunohistochemistry and RT-PCR were used. KEY RESULTS: Infiltration of CD3+ T-cells in the remnant kidney was increased after 5/6 nephrectomy in wildtype mice, along with a robust induction of IL-17A production in CD4+ T and γδ T-cells. After 5/6 nephrectomy, wildtype mice developed albuminuria in the nephrotic range over 10 weeks. This was accompanied by severe glomerular sclerosis and tubulointerstitial injury, and as well as renal mRNA expression of markers of inflammation and fibrosis (the chemokine CCL2, plasminogen activator inhibitor-1; PAI-1 and neutrophil gelatinase-associated lipocalin; NGAL). Unexpectedly, RAG-1 deficient mice and IL-17A deficient mice developed renal injury, similar to that in wildtype mice. No differences were found for albuminuria, glomerular sclerosis, tubulointerstitial injury and mRNA expression of CCL2, PAI-1 and NGAL. Mortality did not differ between the three groups. CONCLUSIONS AND IMPLICATIONS: Numbers of CD3+ T-cells and IL-17A+ lymphocytes infiltrating the kidney were increased after 5/6 nephrectomy. In contrast to other experimental models of renal injury, genetic deficiency of the adaptive immune system or of IL-17A did not attenuate induction or progression of chronic kidney disease after 5/6 nephrectomy. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

The chemokine receptor CX3CR1 reduces renal injury in mice with angiotensin II-induced hypertension.

The role of CX3CR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CX3CR1 in hypertensive renal and cardiac injury. Expression of CX3CR1 was determined using CX3CR1GFP/+ mice that express a green fluorescent protein (GFP) reporter in CX3CR1+ cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45+ cells expressed CX3CR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%), and T cells (10%). With the use of confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CX3CR1 in hypertensive end-organ injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of angiotensin II (ANG II, 1.5 ng·g-1·min-1) and a high-salt diet in wild-type ( n = 15) and CX3CR1-deficient mice ( n = 18). CX3CR1 deficiency reduced the number of renal dendritic cells and increased the numbers of renal CD11b/F4/80+ macrophages and CD11b/Ly6G+ neutrophils in ANG II-infused mice. Surprisingly, CX3CR1-deficient mice exhibited increased albuminuria, glomerular injury, and reduced podocyte density in spite of similar levels of arterial hypertension. In contrast, cardiac damage as assessed by increased heart weight, cardiac fibrosis, and expression of fetal genes, and matrix components were not different between both genotypes. Our findings suggest that CX3CR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CX3CR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury.

Ubiquitin C-Terminal Hydrolase L1 is required for regulated protein degradation through the ubiquitin proteasome system in kidney.

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a major deubiquitinating enzyme of the nervous system and associated with the development of neurodegenerative diseases. We have previously shown that UCH-L1 is found in tubular and parietal cells of the kidney and is expressed de novo in injured podocytes. Since the role of UCH-L1 in the kidney is unknown we generated mice with a constitutive UCH-L1-deficiency to determine its role in renal health and disease. UCH-L1-deficient mice developed proteinuria, without gross changes in glomerular morphology. Tubular cells, endothelial cells, and podocytes showed signs of stress with an accumulation of oxidative-modified and polyubiquitinated proteins. Mechanistically, abnormal protein accumulation resulted from an altered proteasome abundance leading to decreased proteasomal activity, a finding exaggerated after induction of anti-podocyte nephritis. UCH-L1-deficient mice exhibited an exacerbated course of disease with increased tubulointerstitial and glomerular damage, acute renal failure, and death, the latter most likely a result of general neurologic impairment. Thus, UCH-L1 is required for regulated protein degradation in the kidney by controlling proteasome abundance. Altered proteasome abundance renders renal cells, particularly podocytes and endothelial cells, susceptible to injury.