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NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice.

ABSTRACT: Renal tubulointerstitial lesions (TILs), a common pathologic hallmark of chronic kidney disease that evolves to end-stage renal disease, is characterized by progressive inflammation and pronounced fibrosis of the kidney. However, current therapeutic approaches to treat these lesions remain largely ineffectual. Previously, we demonstrated that elevated IL-36α levels in human renal tissue and urine are implicated in impaired renal function, and IL-36 signaling enhances activation of NLRP3 inflammasome in a mouse model of TILs. Recently, we synthesized NSC828779, a salicylanilide derivative (protected by U.S. patents with US 8975255 B2 and US 9162993 B2), which inhibits activation of NF-κB signaling with high immunomodulatory potency and low IC₅₀, and we hypothesized that it would be a potential drug candidate for renal TILs. The current study validated the therapeutic effects of NSC828779 on TILs using a mouse model of unilateral ureteral obstruction (UUO) and relevant cell models, including renal tubular epithelial cells under mechanically induced constant pressure. Treatment with NSC828779 improved renal lesions, as demonstrated by dramatically reduced severity of renal inflammation and fibrosis and decreased urinary cytokine levels in UUO mice. This small molecule specifically inhibits the IL-36α/NLRP3 inflammasome pathway. Based on these results, the beneficial outcome represents synergistic suppression of both the IL-36α-activated MAPK/NLRP3 inflammasome and STAT3- and Smad2/3-dependent fibrogenic signaling. NSC828779 appears justified as a new drug candidate to treat renal progressive inflammation and fibrosis.

SUBMITTER: Yang SR

PROVIDER: S-EPMC8623783 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRenal tubules and interstitium are vulnerable to injury and play a central role in the progression of various chronic kidney diseases (CKDs). However, high quality epidemiologic study on the profiles of biopsy-proven tubulointerstitial lesions (TILs) is extremely limited.MethodsWe conducted a retrospective renal biopsy series including 62,569 native biopsies at 1,211 hospitals across China from 2015 to 2017. The TILs, including the shedding of tube epithelial, renal tubular atrophy, renal interstitial fibrosis, edema and inflammatory infiltration, were identified from the pathological report. We analyzed the severity and chronicity of TILs stratified by gender, age groups, biopsy indications, and concurrent glomerular diseases. We also examined the correlation between TIL and glomerulosclerosis.ResultsOf 56,880 patients with biopsy-proven glomerular disease, 79.5% had TILs. Renal interstitial inflammatory infiltration was the most common type of TIL (77.7%), followed by renal tubular atrophy (56.0%) and renal interstitial fibrosis (32.8%). Severe and chronic TILs were more common in adults than in children. The three glomerular diseases with the highest proportion of moderate-to-severe and chronic TIL were diabetic nephropathy, immunoglobulin A (IgA) nephropathy and focal segmental glomerulosclerosis. The severity of TILs was moderately correlated with glomerulosclerosis score (r=0.51). Moderate-to-severe and chronic TIL were more common in southern China. After adjusting for age, sex, hospital level, region, biopsy indication and type of concurrent glomerular diseases, adults with renal arteriole injury had a six-fold higher risk of moderate-to-severe TIL [odds ratio (OR), 7.12; 95% confidence interval (CI), 6.42 to 7.91] and a three-fold higher risk of chronic TIL (OR, 4.58; 95% CI, 4.37 to 4.79).ConclusionsTILs were common in patients with biopsy-proven glomerular disease. The type and severity of TILs varied with age, region and concurrent glomerular diseases. Renal arteriole injury and glomerulosclerosis was associated with a significantly increased risk of TIL.

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NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice.

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