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Blockade of the natriuretic peptide clearance receptor attenuates proteinuria in a mouse model of focal segmental glomerulosclerosis

ABSTRACT: Abstract Glomerular podocytes play a key role in proteinuric diseases. Accumulating evidence suggests that cGMP signaling has podocyte protective effects. The major source of cGMP generation in podocytes is natriuretic peptides. The natriuretic peptide clearance receptor (NPRC) binds and degrades natriuretic peptides. As a result, NPRC inhibits natriuretic peptide‐induced cGMP generation. To enhance cGMP generation in podocytes, we blocked natriuretic peptide clearance using the specific NPRC ligand ANP(4‐23). We then studied the effects of NPRC blockade in both cultured podocytes and in a mouse transgenic (TG) model of focal segmental glomerulosclerosis (FSGS) created in our laboratory. In this model, a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria in TG mice, but only mild disease in non‐TG animals. We found that natriuretic peptides protected cultured podocytes from PAN‐induced apoptosis, and that ANP(4‐23) enhanced natriuretic peptide‐induced cGMP generation in vivo. PAN‐induced heavy proteinuria in vehicle‐treated TG mice, and this increase in albuminuria was reduced by treatment with ANP(4‐23). Treatment with ANP(4‐23) also reduced the number of mice with glomerular injury and enhanced urinary cGMP excretion, but these differences were not statistically significant. Systolic BP was similar in vehicle and ANP(4‐23)‐treated mice. These data suggest that: 1. Pharmacologic blockade of NPRC may be useful for treating glomerular diseases such as FSGS, and 2. Treatment outcomes might be improved by optimizing NPRC blockade to inhibit natriuretic peptide clearance more effectively. The effects of blocking natriuretic peptide clearance from the circulation was examined in a mouse model of focal segmental glomerulosclerosis (FSGS). We found that blockade of the natriuretic clearance receptor protected glomerular podocytes from apoptosis and inhibited albuminuria in FSGS.

SUBMITTER: Wang L

PROVIDER: S-EPMC8578888 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale & objectiveRemission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival.Study designCohort analysis of clinical trial participants.Setting & participantsPatients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone.PredictorsReduction in proteinuria measured during 26 weeks after initiating treatment.OutcomesRepeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization.Analytical approachMultivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome.Results138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44).LimitationsLimited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years.ConclusionsThese findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

Project description:BACKGROUND AND OBJECTIVES:Proteinuria is used as an indicator of FSGS disease activity, but its use as a clinical trial end point is not universally accepted. The goal of this study was to refine proteinuria definitions associated with long-term kidney survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Data on 466 patients with primary FSGS with proteinuria (urine protein-to-creatinine ratio >1 g/g) were analyzed from five independent cohorts. Proteinuria by months 1, 4, and 8 after study baseline was categorized by conventional definitions of complete (<0.3 g/g) and partial remission (<3.5 g/g and 50% reduction in proteinuria). Novel remission definitions were explored using receiver operating curves. Kaplan-Meier methods were used to estimate the associations of proteinuria with progression to ESRD or a 50% loss in kidney function. Propensity score-adjusted Cox proportional hazards models were used to adjust for baseline proteinuria, eGFR, and therapy. RESULTS:In the initial derivation cohort, conventional partial remission was not associated with kidney survival. A novel definition of partial remission (40% proteinuria reduction and proteinuria<1.5 g/g) on the basis of receiver operating curve analyses of 89 patients was identified (Sensitivity=0.70; Specificity=0.77). In the validation cohort analyses, complete remission was associated with better prognosis (6 out of 41 patients progressed to kidney failure; 6.6 per 100 patient-years) as was the novel partial remission (13 out of 71 progressed; 8.5 per 100 patient-years), compared with those with no response (51 out of 116 progressed; 20.1 per 100 patient-years). Conventional partial remission at month 8, but not month 4, was also associated with better response (19 out of 85 patients progressed; risk=10.4 per 100 patient-years). Propensity score-adjusted analyses showed the novel partial remission was associated with less progression at months 4 and 8 (month 4: hazard ratio, 0.50; P=0.01; month 8: hazard ratio, 0.30; P=0.002). CONCLUSIONS:Reaching either a complete or partial remission using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS. PODCAST:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_02_20_CJASNPodcast_18_3_T.mp3.

Project description:Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

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Blockade of the natriuretic peptide clearance receptor attenuates proteinuria in a mouse model of focal segmental glomerulosclerosis

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