Dyslipidemia–Renin–Angiotensin System Crosstalk in Diabetic Kidney Disease: A Critical Narrative Review of Experimental Mechanisms and Clinical Evidence Publisher

Summary: Do cholesterol and hormone pathways interact in diabetic kidney disease? A review proposes a dyslipidemia–RAS link, but says human evidence cannot prove this pathway. #KidneyHealth #Diabetes

Nasri H ; Chitsazi M R ; Abbasi F ; Ashouri A H ; Rouzbahani H ; Mirzaei S A ; Golafshan F ; Noursina A ; Safari F
Source: Bratislava Medical Journal Published:2026

Abstract

Diabetic kidney disease (DKD) is phenotypically heterogeneous and may present with albuminuria, loss of estimated glomerular filtration rate (eGFR), or both. Dyslipidemia and renin–angiotensin system (RAS) activation coexist in many patients, but the extent to which they form a self-sustaining pathogenic circuit in human DKD remains uncertain. We conducted a critical narrative review supported by a structured search of PubMed/MEDLINE, ClinicalTrials.gov, and official guideline repositories from database inception to 1 August 2026. Randomized clinical trials, human observational and mechanistic studies, and directly relevant experimental studies were prioritized and classified by evidence domain. Experimental work supports bidirectional crosstalk: oxidized lipoproteins can stimulate renin release in isolated juxtaglomerular cells, whereas angiotensin II can impair renal lipid handling, promote cholesterol accumulation, and amplify oxidative, inflammatory, mitochondrial, and fibrotic signaling. The recently proposed angiotensin II type 1 receptor–lectin-like oxidized low-density lipoprotein receptor-1 (AT1R–LOX-1) complex offers a plausible molecular bridge, but current evidence derives mainly from engineered cell systems and non-diabetic mouse models. Similarly, epigenetic memory, urinary renin, and epithelial plasticity are biologically relevant research areas but are not yet validated as DKD-specific therapeutic or diagnostic tools. Clinical outcome evidence is strongest for layered cardio–kidney therapy using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in appropriate patients, sodium–glucose cotransporter 2 inhibitors, the non-steroidal mineralocorticoid receptor antagonist finerenone, and glucagon-like peptide-1 receptor agonists. FLOW established kidney-outcome benefit for semaglutide, while the peer-reviewed REMODEL design illustrates how kidney mechanisms can be interrogated without substituting mechanistic inference for outcomes. Tirzepatide and triple incretin agonists show encouraging but still exploratory kidney signals; aldosterone synthase inhibitors reduce albuminuria in phase 2 studies but lack hard-outcome evidence. The dyslipidemia–RAS network is therefore best regarded as an evidence-calibrated framework for hypothesis generation and therapeutic integration, not as a clinically proven linear pathway. © The Author(s), under exclusive licence to the Faculty of Medicine, Comenius University in Bratislava 2026.