Cited by 18Chronic Kidney Disease and DiabetesRenal Diseases and GlomerulopathiesNatural Antidiabetic Agents Studies

Glucosidase inhibitor, Nimbidiol ameliorates renal fibrosis and dysfunction in type-1 diabetes

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Juin, Subir Kumar, Pushpakumar, Sathnur, Tyagi, Suresh C., Sen, Utpal·2022·Scientific Reports

Abstract

Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) leading to renal fibrosis, progressive deterioration of renal function, and eventually to end stage renal disease. Matrix metalloproteinases (MMPs) are known to regulate synthesis and degradation of the ECM. Earlier, we demonstrated that imbalanced MMPs promote adverse ECM remodeling leading to renal fibrosis in type-1 diabetes. Moreover, elevated macrophage infiltration, pro-inflammatory cytokines and epithelial‒mesenchymal transition (EMT) are known to contribute to the renal fibrosis. Various bioactive compounds derived from the medicinal plant, Azadirachta indica (neem) are shown to regulate inflammation and ECM proteins in different diseases. Nimbidiol is a neem-derived diterpenoid that is considered as a potential anti-diabetic compound due to its glucosidase inhibitory properties. We investigated whether Nimbidiol mitigates adverse ECM accumulation and renal fibrosis to improve kidney function in type-1 diabetes and the underlying mechanism. Wild-type (C57BL/6J) and type-1 diabetic (C57BL/6‐Ins2Akita/J) mice were treated either with saline or with Nimbidiol (0.40 mg kg−1 d−1) for eight weeks. Diabetic kidney showed increased accumulation of M1 macrophages, elevated pro-inflammatory cytokines and EMT. In addition, upregulated MMP-9 and MMP-13, excessive collagen deposition in the glomerular and tubulointerstitial regions, and degradation of vascular elastin resulted to renal fibrosis in the Akita mice. These pathological changes in the diabetic mice were associated with functional impairments that include elevated resistive index and reduced blood flow in the renal cortex, and decreased glomerular filtration rate. Furthermore, TGF-β1, p-Smad2/3, p-P38, p-ERK1/2 and p-JNK were upregulated in diabetic kidney compared to WT mice. Treatment with Nimbidiol reversed the changes to alleviate inflammation, ECM accumulation and fibrosis and thus, improved renal function in Akita mice. Together, our results suggest that Nimbidiol attenuates inflammation and ECM accumulation and thereby, protects kidney from fibrosis and dysfunction possibly by inhibiting TGF-β/Smad and MAPK signaling pathways in type-1 diabetes.

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  • Renal function indicators are highly specific to diabetic nephropathy.

    “Comparative analyses across complications reveal differing key predictors: retinal imaging features are critical for DR [154], renal function indicators are highly specific to DN [155], while hypertension and dyslipidemia serve as strong predictors for CVD [156] but also overlap with DR and DN [157].”

    From Artificial intelligence-powered prediction of diabetic complications: from clinical data to molecular omics (2026) · cites this paper as [155]

    The Results section reports reduced GFR in diabetic mice, supporting the relevance of renal function indicators to diabetic nephropathy. It does not establish that those indicators are highly specific to diabetic nephropathy; the Discussion also associates increased renal resistive index and poor renal function with chronic kidney disease more broadly. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Authors
Juin, S. K., Pushpakumar, S., Tyagi, S. C., & Sen, U.
Affiliations
University of Louisville (US)
Corresponding author
Sen, Utpal
Venue
Scientific Reports
Published
2022-12-15
Volume
12
Issue
1
Pages
21707-21707
ISSN
2045-2322 (ISSN-L)
OpenAlex
W4311749438
Cited by
18
References
104
Citations by year
2026: 4 · 2025: 3 · 2024: 4 · 2023: 7
FWCI
2.22
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (DK116591)
Topics
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords
Azadirachta indica, type 1 diabetes, diabetic nephropathy, renal fibrosis, extracellular matrix accumulation, matrix metalloproteinases, MMP-9, MMP-13, macrophage infiltration, epithelial-mesenchymal transition, TGF-β/Smad signaling, MAPK signaling, glucosidase inhibitors, diterpenoids, Akita mice, renal function
MeSH terms
Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Diterpenes, Fibrosis, Glucosidases, Inflammation, Kidney, Mice, Inbred C57BL, Mice, Transforming Growth Factor beta1

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