Nanocurcumin Combined With Insulin Alleviates Diabetic Kidney Disease Through P38/P53 Signaling Axis

Authors

Raghu Ganugula
Nikhil K Nuthalapati
Subhash Dwivedi
Dianxiong Zou
Meenakshi Arora
Richard Friend
David Sheikh-Hamad
Rita Basu
M N V Ravi Kumar

Publication Date

1-1-2023

Journal

Journal of Controlled Release

DOI

10.1016/j.jconrel.2022.12.012

PMID

36503070

PMCID

PMC9904426

PubMedCentral® Posted Date

1-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Rats, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Hyperglycemia, Inflammation, Insulin, Kidney, Tumor Suppressor Protein p53, p38 Mitogen-Activated Protein Kinases, Diabetic kidney disease, oral delivery, curcumin, bioavailability, insulin, P38(MAPK)/P53 signaling axis, combination therapy, inflammasome

Abstract

Treatments for diabetic kidney disease (DKD) mainly focus on managing hyperglycemia and hypertension, but emerging evidence suggests that inflammation also plays a role in the pathogenesis of DKD. This 10-week study evaluated the efficacy of daily oral nanoparticulate-curcumin (nCUR) together with long-acting insulin (INS) to treat DKD in a rodent model. Diabetic rats were dosed with unformulated CUR alone, nCUR alone or together with INS, or INS alone. The progression of diabetes was reflected by increases in plasma fructosamine, blood urea nitrogen, creatinine, bilirubin, ALP, and decrease in albumin and globulins. These aberrancies were remedied by nCUR+INS or INS but not by CUR or nCUR. Kidney histopathological results revealed additional abnormalities characteristic of DKD, such as basement membrane thickening, tubular atrophy, and podocyte cytoskeletal impairment. nCUR and nCUR+INS mitigated these lesions, while CUR and INS alone were far less effective, if not ineffective. To elucidate how our treatments modulated inflammatory signaling in the liver and kidney, we identified hyperactivation of P38 (MAPK) and P53 with INS and CUR, whereas nCUR and nCUR+INS deactivated both targets. Similarly, the latter interventions led to significant downregulation of renal NLRP3, IL-1β, NF-ĸB, Casp3, and MAPK8 mRNA, indicating a normalization of inflammasome and apoptotic pathways. Thus, we show therapies that reduce both hyperglycemia and inflammation may offer better management of diabetes and its complications.

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