Proprotein convertase subtilisin/kexin type 9 targets megalin in the kidney proximal tubule and aggravates proteinuria in nephrotic syndrome

Skeby, Cecilie K.; Hummelgaard, Sandra; Gustafsen, Camilla; Petrillo, Federica; Frederiksen, Kristen; Olsen, Ditte; Kristensen, Tilde; Ivarsen, Per; Madsen, Peder; Christensen, Erik; Nielsen, Rikke; Birn, Henrik; Glerup, Simon; Weyer, Kathrin

doi:10.1016/j.kint.2023.06.024

Cited by 10 publications

(2 citation statements)

References 79 publications

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“…[49][50][51][52][53] Especially promising is the interaction between megalin and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, where PCSK9 inhibition increased kidney megalin and reduced urinary albumin excretion in nephrotic mice, potentially providing renal protection. [54] Thus, modulation of megalin/cubilin expression [54,55] or the interaction between megalin/cubilin and nephrotoxic drugs [56] may be important components of protection from and recovery/regeneration after injury. [49] FUTURE DIRECTIONS There are a number of questions and/or directions for future investigation.…”

Section: Megalin Is Involved In the Regulation Of Mitochondrial Metab...mentioning

confidence: 99%

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Li,

Sheikh-Hamad

2023

Integr Med Nephrol Androl

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Megalin (also known as low density lipoprotein-receptor related protein 2 [LRP2]) is a multi-ligand cell-surface endocytic receptor expressed widely; it is important for the uptake of vitamins, nutrients and hormones. We recently reported the discovery of LRP2/megalin in the mitochondria of many cells and organs. Importantly, megalin traffics the mitochondrial intracrines stanniocalcin-1, TGF-β and angiotensin II from the extracellular milieu to the mitochondria. This transport parallels the retrograde early endosome to Golgi pathway and requires the Rab GTPase Rab32 in the mitochondria, megalin associates with sirtuin family of class III histone deacetylases (Sirt3) and stanniocalcin-1 (Stc1), which are important for anti-oxidant defenses. Deletion of megalin impairs mitochondrial respiration and glycolysis. The interaction between stanniocalcin-1 and megalin is mediated by leucines within the signal peptides of the proteins; and this interaction is essential to the stimulation of mitochondrial respiration and glycolysis by stanniocalcin-1. Our findings suggest that megalin facilitates the regulation of mitochondrial function by extracellular cues.

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Section: Megalin Is Involved In the Regulation Of Mitochondrial Metab...mentioning

confidence: 99%

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Li,

Sheikh-Hamad

2023

Integr Med Nephrol Androl

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“… 25 , 26 On the other hand, preserving megalin expression by inhibiting proprotein convertase subtilisin/kexin type 9 in proteinuric animals is protective in dampening renal fibrosis and other injury markers. 27 The expression of megalin is affected in diseases such as T2D, with unknown consequences to disease progression. 28 , 29 …”

Section: Introductionmentioning

confidence: 99%

Megalin Knockout Reduces SGLT2 Expression and Sensitizes to Western Diet-induced Kidney Injury

Youm,

Shipman,

Albalawy

et al. 2024

Function

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Megalin (Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. Studies in our lab have shown that knock out (KO) of Lrp2 in opossum PT cells leads to a dramatic reduction in sodium glucose co-transporter 2 (SGLT2) transcript and protein levels, as well as differential expression of genes involved in mitochondrial and metabolic function. SGLT2 transcript levels are reduced more modestly in Lrp2 KO mice. Here, we investigated the effects of Lrp2 KO on kidney function and health in mice fed regular chow (RC) or a Western-style diet (WD) high in fat and refined sugar. Despite a modest reduction in SGLT2 expression, Lrp2 KO mice on either diet showed increased glucose tolerance compared to control mice. Moreover, Lrp2 KO mice were protected against WD-induced fat gain. Surprisingly, renal function in male Lrp2 KO mice on WD was compromised, and the mice exhibited significant kidney injury compared with control mice on WD. Female Lrp2 KO mice were less susceptible to WD-induced kidney injury than male Lrp2 KO. Together, our findings reveal both positive and negative contributions of megalin expression to metabolic health, and highlight a megalin-mediated sex-dependent response to injury following WD.

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Drug repurposing for glomerular diseases: an underutilized resource

Ng,

Kaur,

Francis

et al. 2024

Nat Rev Nephrol

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Proprotein convertase subtilisin/kexin type 9 targets megalin in the kidney proximal tubule and aggravates proteinuria in nephrotic syndrome

Cited by 10 publications

References 79 publications

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Megalin Knockout Reduces SGLT2 Expression and Sensitizes to Western Diet-induced Kidney Injury

Drug repurposing for glomerular diseases: an underutilized resource

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