Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms

Abstract

Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD’s tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.

Nephroprotective Effect of Hibiscus Sabdariffa Leaf Flavonoid Extracts via KIM-1 and TGF-1β Signaling Pathways in Streptozotocin-Induced Rats

“…IL-1β, IL-6, and TNF-α play vital roles in immune cell regulation, inflammation modulation, and tissue repair in response to injury or infection. − In pathological conditions such as kidney diseases, the expression of these inflammatory biomarkers can become dysregulated, leading to an overactive immune response and chronic inflammation. Elevated levels of IL-1β, IL-6, and TNF-α in the kidneys may contribute to tissue damage, fibrosis, and the progression of various kidney disorders, including glomerulonephritis, tubulointerstitial nephritis, and diabetic nephropathy. − It is very important to note that monitoring the physiological levels of these inflammatory biomarkers helps in understanding the immune response in kidney pathology and can thus guide therapeutic interventions to mitigate inflammation and prevent further damage . Treatment with HSLF and metformin was able to significantly ( p < 0.05) reverse these harmful increases in pro-inflammatory biomarker levels, suggesting an anti-inflammatory effect of the HSLF.…”

“…Elevated levels of IL-1β, IL-6, and TNF-α in the kidneys may contribute to tissue damage, fibrosis, and the progression of various kidney disorders, including glomerulonephritis, tubulointerstitial nephritis, and diabetic nephropathy. 58 − 60 It is very important to note that monitoring the physiological levels of these inflammatory biomarkers helps in understanding the immune response in kidney pathology and can thus guide therapeutic interventions to mitigate inflammation and prevent further damage. 61 Treatment with HSLF and metformin was able to significantly ( p < 0.05) reverse these harmful increases in pro-inflammatory biomarker levels, suggesting an anti-inflammatory effect of the HSLF.…”

The role of long non‐coding RNAs in the development of diabetic kidney disease and the involved clinical application

“…102 Renal tubular structural changes during the development of DKD mainly include tubular cell proliferation and hypertrophy, tubular atrophy, tubular basement membrane thickening, and EMT, leading to interstitial fibrosis. 103 In particular, EMT is the process by which epithelial cells become mesenchymal cells characterised by the absence of epithelial cell markers and the upregulation of the expression of mesenchymal cell markers. 104 Several scholars have reported that DKD-related lncRNAs are associated with renal tubular cell (RTC) injury and mesenchymal fibrosis.…”

“…According to recent research, the renal tubules and interstitium also play a very important role in the pathogenesis of DKD, and renal tubular injury occurs in the early stages of DKD and promotes the progression of renal disease 102 . Renal tubular structural changes during the development of DKD mainly include tubular cell proliferation and hypertrophy, tubular atrophy, tubular basement membrane thickening, and EMT, leading to interstitial fibrosis 103 . In particular, EMT is the process by which epithelial cells become mesenchymal cells characterised by the absence of epithelial cell markers and the upregulation of the expression of mesenchymal cell markers 104 .…”

Transforming Diabetes Care: The Molecular Pathways through Which GLP1-RAs Impact the Kidneys in Diabetic Kidney Disease

“…Glomerular hypertension exerts substantial mechanical stress on the capillary walls, being a precursor to glomerulosclerosis and the depletion of peritubular capillaries. Moreover, it facilitates increased protein filtration into the tubular lumen, which triggers the synthesis of proinflammatory and profibrotic factors with accelerated kidney damage [ 31 ].…”