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HNRNPA1-mediated exosomal sorting of miR-483-5p out of renal tubular epithelial cells promotes the progression of diabetic nephropathy-induced renal interstitial fibrosis.

ABSTRACT: Diabetic nephropathy (DN) is a serious complication in type 1 and type 2 diabetes, and renal interstitial fibrosis plays a key role in DN progression. Here, we aimed to probe into the role and potential mechanism of miR-483-5p in DN-induced renal interstitial fibrosis. In this study, we corroborated that miR-483-5p expression was lessened in type 1 and type 2 diabetic mice kidney tissues and high glucose (HG)-stimulated tubular epithelial cells (TECs), and raised in the exosomes derived from renal tissues in type 1 and type 2 diabetic mice. miR-483-5p restrained the expressions of fibrosis-related genes in vitro and renal interstitial fibrosis in vivo. Mechanistically, miR-483-5p bound both TIMP2 and MAPK1, and TIMP2 and MAPK1 were bound up with the regulation of miR-483-5p on renal TECs under HG conditions. Importantly, HNRNPA1-mediated exosomal sorting transported cellular miR-483-5p out of TECs into the urine. Our results expounded that HNRNPA1-mediated exosomal sorting transported cellular miR-483-5p out of TECs into the urine, thus lessening the restraint of cellular miR-483-5p on MAPK1 and TIMP2 mRNAs, and ultimately boosting extracellular matrix deposition and the progression of DN-induced renal interstitial fibrosis.

SUBMITTER: Liu D

PROVIDER: S-EPMC7946926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study examines the effect of interstitial inflammation and interstitial fibrosis and tubular atrophy on renal survival in lupus nephritis.Baseline characteristics, initial (n = 301) and repeat biopsies (n = 94) and clinical outcomes for patients with biopsy-proven lupus nephritis from 1998 to 2014 were retrospectively collected from the medical record. Clinical and morphologic variables were evaluated using a Cox proportional hazards model and multiple imputation to address missing data. Renal survival was defined as the time from initial biopsy to end-stage renal disease [estimated glomerular filtration rate (eGFR) <15?mL/min/1.73 m2], dialysis or transplant.A total of 218 patients had follow-up and Class IV had worse renal survival, especially in patients with active and chronic glomerular lesions {relative to non-IV; Class IV-A: hazard ratio [HR] 0.92 [95% confidence interval (CI) 0.41-2.04], Class IV-AC: HR 5.02 [95% CI 2.70-9.36]}. Interstitial inflammation grade [relative to interstitial inflammation <5%; interstitial inflammation 5-25%: HR 2.36 (95% CI 1.13-4.91), interstitial inflammation 25-50%: HR 3.84 (95% CI 1.53-9.62), interstitial inflammation >50%: HR 7.67 (95% CI 3.75-15.67)] and increased interstitial fibrosis and tubular atrophy (IFTA) category [relative to IFTA <5%; IFTA 5-25%: HR 3.93 (95% CI 1.58-9.75), IFTA 25-50%: HR 4.01 (95% CI 1.37-11.70), IFTA >50%: HR 13.99 (95% CI 4.91-39.83)] predicted worse renal survival among all patients and those with Class IV on initial and repeat biopsy (n = 94) in a dose-dependent manner. Interstitial inflammation grade and IFTA category were significant predictors of renal survival in a multivariable model adjusted for age, gender, race, ethnicity and serum creatinine.Interstitial inflammation and IFTA independently affect renal survival and grading these lesions stratifies risk within the International Society of Nephrology and Renal Pathology Society classification of lupus nephritis.

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HNRNPA1-mediated exosomal sorting of miR-483-5p out of renal tubular epithelial cells promotes the progression of diabetic nephropathy-induced renal interstitial fibrosis.

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