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Novel Immunomodulatory Cytokine Regulates Inflammation, Diabetes, and Obesity to Protect From Diabetic Nephropathy.

ABSTRACT: Obesity-linked (type 2) diabetic nephropathy (T2DN) has become the largest contributor to morbidity and mortality in the modern world. Recent evidences suggest that inflammation may contribute to the pathogenesis of T2DN and T-regulatory cells (Treg) are protective. We developed a novel cytokine (named IL233) bearing IL-2 and IL-33 activities in a single molecule and demonstrated that IL233 promotes Treg and T-helper (Th) 2 immune responses to protect mice from inflammatory acute kidney injury. Here, we investigated whether through a similar enhancement of Treg and inhibition of inflammation, IL233 protects from T2DN in a genetically obese mouse model, when administered either early or late after the onset of diabetes. In the older mice with obesity and microalbuminuria, IL233 treatment reduced hyperglycemia, plasma glycated proteins, and albuminuria. Interestingly, IL233 administered before the onset of microalbuminuria not only strongly inhibited the progression of T2DN and reversed diabetes as indicated by lowering of blood glucose, normalization of glucose tolerance and insulin levels in islets, but surprisingly, also attenuated weight gain and adipogenicity despite comparable food intake. Histological examination of kidneys showed that saline control mice had severe inflammation, glomerular hypertrophy, and mesangial expansion, which were all attenuated in the IL233 treated mice. The protection correlated with greater accumulation of Tregs, group 2 innate lymphoid cells (ILC2), alternately activated macrophages and eosinophils in the adipose tissue, along with a skewing toward T-helper 2 responses. Thus, the novel IL233 cytokine bears therapeutic potential as it protects genetically obese mice from T2DN by regulating multiple contributors to pathogenesis. Short Description: A novel bifunctional cytokine IL233, bearing IL-2 and IL-33 activities reverses inflammation and protects from type-2 diabetic nephropathy through promoting T-regulatory cells and type 2 immune response.

SUBMITTER: Sabapathy V

PROVIDER: S-EPMC6540785 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Novel Immunomodulatory Cytokine Regulates Inflammation, Diabetes, and Obesity to Protect From Diabetic Nephropathy.

Sabapathy Vikram V Stremska Marta E ME Mohammad Saleh S Corey Rebecca L RL Sharma Poonam R PR Sharma Rahul R

Frontiers in pharmacology 20190522

Obesity-linked (type 2) diabetic nephropathy (T2DN) has become the largest contributor to morbidity and mortality in the modern world. Recent evidences suggest that inflammation may contribute to the pathogenesis of T2DN and T-regulatory cells (Treg) are protective. We developed a novel cytokine (named IL233) bearing IL-2 and IL-33 activities in a single molecule and demonstrated that IL233 promotes Treg and T-helper (Th) 2 immune responses to protect mice from inflammatory acute kidney injury. ...[more]

PMID: 31191312

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Project description:BackgroundThe epidemic of diabetic nephropathy (DN) has been paralleled by rapid increases in both obesity and diabetes in China. The aim of this study was to investigate the natural history of DN and the association of obesity and renal function with diabetes.MethodsIn total, 264 patients with renal biopsy-confirmed DN were examined from 2002 to 2008 and followed up to June 2008 in our institute. Among these, 129 patients were classified into a Kidney Disease Outcomes Quality Initiative (K/DOQI) stage I subgroup. Weight status, clinico-histopathological features, the development of end-stage renal disease (ESRD) and increased proteinuria were evaluated at the baseline of biopsy and during the follow up. Lean, overweight and obese phenotypes were defined as body mass index (BMI) less than 25 kg/m2, 25-28 kg/m2, and more than 28 kg/m2 over, respectively.ResultsIn the patients with renal biopsy-confirmed DN, BMI was 25.5 ± 3.39 kg/m2, with 122 (46.2%), 83 (31.4%) and 59 (22.3%) having lean, overweight and obese phenotypes, respectively. Mean proteinuria was 3.09 ± 2.32 g/24 h, serum creatinine was 2.02 ± 2.02 mg/dL, and creatinine clearance rate (Ccr) was 96.0 ± 54.0 mL/min/1.73 m2. Compared with obese patients, lean patients had a lower Ccr, a higher percentage of anemia, more renal lesions and higher risk for ESRD (HR = 1.812, P = 0.048). The weight in obese patients decreased significantly after 27 months, and lean patients had a longer duration of diabetes than obese patients. Regarding patients at K/DOQI stage I, patients with DN showed similar duration of diabetes regardless of weight status. Minimal weight loss was recorded in obese patients during follow-up, and they exhibited greater glomerular hyperfiltration and higher risk for increased proteinuria (HR = 2.872, P = 0.014) than lean patients.ConclusionsIn China, obesity is common in DN patients undergoing biopsy. Initial high levels of proteinuria and subsequent weight loss are the major characteristics of the natural course of DN. Obesity contributed to increased proteinuria at an early stage, while the lean phenotype was associated with ESRD development, especially at the later stages.

Dataset Information

Novel Immunomodulatory Cytokine Regulates Inflammation, Diabetes, and Obesity to Protect From Diabetic Nephropathy.

Publications

Novel Immunomodulatory Cytokine Regulates Inflammation, Diabetes, and Obesity to Protect From Diabetic Nephropathy.

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