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Increased SGK1 activity potentiates mineralocorticoid/NaCl-induced hypertension and kidney injury

Catalina Sierra-Ramos, Silvia Velazquez-Garcia, Ayse G. Keskus, Arianna Vastola-Mascolo, Ana E. Rodríguez-Rodríguez, Sergio Luis-Lima, Guadalberto Hernández,, Juan F. Navarro-González, Esteban Porrini, Ozlen Konu, Diego Alvarez de la Rosa

Preprint posted on July 09, 2020 https://www.biorxiv.org/content/10.1101/2020.07.08.191874v1

SGK1 transgenic mice develop mineralocorticoid/salt-induced hypertension

Selected by Nándor Lipták

Background

The serum and glucocorticoid-induced kinase 1 (SGK1), member of the AGC family of S/T kinases is activated by insulin and growth factors, such as insulin-like growth factor-1, via the phosphatidylinositol 3-kinase (PI3K) pathway. SGK1 increases aldosterone-dependent renal Na+ reabsorption and modulates blood pressure. Increased SGK1 expression was detected in renal biopsies of patients suffering from heavy proteinuria, suggesting the detrimental role of SGK1 in various renal diseases (1). Previous reports revealed that wild type (WT) mice, subjected to DOCA/high-salt drinking or diet showed significantly higher blood pressure and urinary albumin/creatinine ratio compared with SGK1 knock-out (KO) mice (2,3). In a recent study, which was done by the researchers of the discussed preprint, SGK1 transgenic (TG) mice fed with high-fat diet developed metabolic syndrome, characterized by obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension (4).

The goal of this preprint was to clarify if the TG overexpression of SGK1 could worsen the hypertension evoked by high-salt drinking and unilateral nephrectomy (NPX) in mice.

 

Key findings

In the discussed preprint, NPX and/or 1% NaCl drinking water and 75 mg/kg BW deoxycorticosterone acetate (DOCA) treatment were performed to evaluate the differences between SGK1 and WT mice in hypertension and renal function.

Blood pressure increase and albuminuria in NPX SGK1 TG mice treated with DOCA/NaCl

NPX alone had no significant effect on blood pressure either in SGK1 TG or WT mice, but a marked increase was observed in SGK1 TG mice compared with WT mice after DOCA/NaCl treatment.

The combination of NPX and DOCA/NaCl also evoked more severe albuminuria in SGK1 TG compared with WT mice.

Glomerular hypertrophy, fibrosis and inflammation after NPX and DOCA/NaCl treatment

The combination of NPX and DOCA/NaCl induced significant glomerular and tubuloinsterstitial fibrosis in SGK1 TG compared to WT mice. Perivascular fibrosis was also marked but not significant in SGK1 TG compared to WT mice.

Whole-transcriptome changes in the renal cortex of SGK1 TG and WT mice

Overall, 120 genes were up-regulated and 78 genes were down-regulated after NPX and DOCA/NaCl treatment. 5 upregulated genes (Cpb2, Lyplal1, Serpina3b, Ccl28 and Col27a1) and 1 down-regulated gene (Adamtsl2) were selected to confirm microarray data by rt-qPCR. NPX and DOCA/NaCl treatment induced a significant increase of Col27a1 mRNA expression in SKG1 TG but in WT mice. Cpb2, Lyplal1, Serpina3b and Ccl28 mRNA expression were higher in SGK1 TG compared to WT mice following NPX, but DOCA/NaCl treatment did not evoke further increase.

 

Why I liked this preprint

SGK1 TG mice may serve as a valuable model for mineralocorticoid/salt-induced hypertension. Moreover, this preprint is a great example of the detailed characterization of a previously created transgenic mouse line.

 

Questions for the authors

  1. Whole-transcriptome analysis was performed using microarrays. In this experimental design, what were the benefits of using microarray technique instead of next generation sequencing?
  2. Besides Sirius-red staining, renal cortex sections are usually stained with Periodic-acid-Schiff to assess glomerular basement membranes. Would it be advantageous to utilize both histological stainings to assess glomerular morphology of SGK1 TG and WT mice?
  3. Was there any difference between SGK1 homozygote and heterozygote TG mice in proteinuria, glomerular damage or hypertension?
  4. In a previous study, SGK1, SGK3 double KO mice had significantly lower blood pressure compared to WT mice after high-salt diet (5). Transgenic overexpression of both SGK1 and SGK3 in mice may evoke more severe hypertension induced by high salt diet and/or NPX?

 

References

  1. Quinkler, M., Zehnder, D., Eardley, K. et al. (2005) Increased expression of mineralocorticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria. Circulation. 112, 1435-1443
  1. Artunc, F., Amann, K., Nasir, O. et al. (2006). Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1. J Mol Med (Berl). 84, 737-746.
  2. Vallon, V., Huang, D. Y., Grahammer, F. et al. (2005). SGK1 as a determinant of kidney function and salt intake in response to mineralocorticoid excess. Am J Physiol Regul Integr Comp Physiol. 289, R395-R401.
  3. Sierra-Ramos, C., Velazquez-Garcia, S., Vastola-Mascolo, A. et al. (2020). SGK1 activation exacerbates diet-induced obesity, metabolic syndrome and hypertension. J Endocrinol. 244, 149-162
  4. Grahammer F, Ferruh Artunc F, Sandulache D. et al. (2006). Renal function of gene-targeted mice lacking both SGK1 and SGK3. Am J Physiol Regul Integr Comp Physiol 290: R945–R950.

 

Posted on: 29th July 2020

doi: Pending

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  • Author's response

    Prof. Diego Alvarez de la Rosa shared

    1.     Whole-transcriptome analysis was performed using microarrays. In this experimental design, what were the benefits of using microarray technique instead of next generation sequencing?

    Answer: NGS (RNAseq) would have also been appropriate for the study. Choosing microarray analysis was based on budget and core service availability.

    2.     Besides Sirius-red staining, renal cortex sections are usually stained with Periodic-acid- Schiff to assess glomerular basement membranes. Would it be advantageous to utilize both histological stainings to assess glomerular morphology of SGK1 TG and WT mice?

    A: Sirius-red staining shows high specificity for collagen fibers, providing a high signal-to-noise, which is an advantage for digital analysis, particularly if fibrosis is in its initial stages and not too developed. Nonetheless, we agree that using additional staining techniques such as PAS would be appropriate in complementing the analysis of glomerular lesions in this model.  

    3.     Was there any difference between SGK1 homozygote and heterozygote TG mice in proteinuria, glomerular damage or hypertension?

    A: We have never studied the phenotype of heterozygous TG mice in detail. This is mainly due to time and budget constraints. In addition, some of the detected phenotypes are relatively mild and therefore may be difficult to detect in heterozygous animals.

    4.     In a previous study, SGK1, SGK3 double KO mice had significantly lower blood pressure compared to WT mice after high-salt diet (5). Transgenic overexpression of both SGK1 and SGK3 in mice may evoke more severe hypertension induced by high salt diet and/or NPX?

    A: In the study by Grahammer et al. using a double SGK1/SGK3 knockout, the main conclusion was that the animals display the phenotypes described for the individual knockouts, but do not show a compound phenotype. SGK3, did not appear to participate in regulating renal sodium handling or blood pressure. Therefore, we think it is unlikely that simultaneous overexpression of both kinases would display more severe hypertension under high salt diet/NPX.

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