ArticleHypertension (Dallas, Tex. : 1979)2019
Podocyte Injury Augments Intrarenal Angiotensin II Generation and Sodium Retention in a Megalin-Dependent Manner.
Article in Hypertension (Dallas, Tex. : 1979), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 31 citations in OpenAlex.
- A novel glomerulopathy model demonstrates renal counterbalance via local angiotensin II regulation.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2025Article
- G protein-coupled receptor 107 deficiency promotes development of diabetic nephropathy.Molecular biomedicine · 2025Article
- Ramipril therapy in integrin α1-null, autosomal recessive Alport mice triples lifespan: mechanistic clues from RNA-seq analysis.The Journal of pathology · 2024Article
- New Approaches Targeting the Renin-Angiotensin System: Inhibition of Brain Aminopeptidase A, ACE2 Ubiquitination, and Angiotensinogen.The Canadian journal of cardiology · 2023Review
- Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes.British journal of pharmacology · 2023Article
- Hepatic and proximal tubule angiotensinogen play distinct roles in kidney dysfunction, glomerular and tubular injury, and fibrosis progression.American journal of physiology. Renal physiology · 2022Article
- Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting.Pharmacological reviews · 2022Review
- Review
- Activation of TRPC6 by AngⅡ Induces Podocyte Injury and Participates in Proteinuria of Nephrotic Syndrome.Frontiers in pharmacology · 2022Article
- Downregulation of megalin, cubilin, ClC-5 and podocin in Fabry nephropathy: potential implications in the decreased effectiveness of enzyme replacement therapy.Journal of nephrology · 2021Article
- Megalin, Proton Pump Inhibitors and the Renin-Angiotensin System in Healthy and Pre-Eclamptic Placentas.International journal of molecular sciences · 2021Article
- The evolving complexity of the collecting duct renin-angiotensin system in hypertension.Nature reviews. Nephrology · 2021Review
- Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?Current hypertension reports · 2020Review
- IL-4 Receptor α Chain Protects the Kidney Against Tubule-Interstitial Injury Induced by Albumin Overload.Frontiers in physiology · 2020Article
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
Abstract
We have previously shown that podocyte injury increases the glomerular filtration of liver-derived Agt (angiotensinogen) and the generation of intrarenal Ang II (angiotensin II) and that the filtered Agt is reabsorbed by proximal tubules in a manner dependent on megalin. In the present study, we aimed to study the role of megalin in the generation of renal Ang II and sodium handling during nephrotic syndrome. We generated proximal tubule-specific megalin KO (knockout) mice and crossed these animals with NEP25 mice, in which podocyte-specific injury can be induced by injection of the immunotoxin LMB2. Without podocyte injury, renal Agt staining was markedly diminished and urinary Agt increased in KO mice. However, renal Ang II was similar between KO and control mice on average: 117 (95% CI, 101-134) versus 101 (95% CI, 68-133) fmol/g tissue. We next tested the effect of megalin KO on intrarenal Ang II generation with podocyte injury. Control NEP25 mice showed markedly increased renal Agt staining and renal Ang II levels: 450 (336-565) fmol/g tissue. Megalin KO/NEP25 mice showed markedly diminished Agt reabsorption and attenuated renal Ang II: 199 (156-242) fmol/g tissue (P<0.001). Compared with control NEP25 mice, megalin KO/NEP25 mice excreted 5-fold more sodium in the urine. Western blot analysis showed that megalin KO decreased NHE3 and the cleaved α and γ forms of Epithelial Na Channel. These data indicate that Agt reabsorbed by proximal tubules via megalin in nephrotic syndrome is converted to Ang II, which may contribute to sodium retention and edema formation by activating NHE3 and Epithelial Na Channel.
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