Salt stress in the renal tubules is linked to TAL-specific expression of uromodulin and an upregulation of heat shock genes

Graham, Lesley; Aman, Alisha; Campbell, Desmond; Augley, Julian J.; Graham, Delyth; McBride, Martin W.; Fraser, Niall J.; Ferreri, Nicholas R.; Dominiczak, Anna F.; Padmanabhan, Sandosh

doi:10.1152/physiolgenomics.00057.2018

Cited by 8 publications

(5 citation statements)

References 52 publications

(62 reference statements)

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“…The normal kidney is constantly under metabolite-, toxin-, and hypoxia-invoked stresses. [52][53][54][55] Our genetic studies highlight Gdf15 as a stress response gene. Using a newly generated, sensitive recombination-mediated reporter, we identified several normal domains of Gdf15 expression.…”

Section: Discussionmentioning

confidence: 85%

Renoprotective and Immunomodulatory Effects of GDF15 following AKI Invoked by Ischemia-Reperfusion Injury

Liu

Kumar

Heinzel

et al. 2020

JASN

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BackgroundGdf15 encodes a TGF-β superfamily member that is rapidly activated in response to stress in multiple organ systems, including the kidney. However, there has been a lack of information about Gdf15 activity and effects in normal kidney and in AKI.MethodsWe used genome editing to generate a Gdf15nuGFP-CE mouse line, removing Gdf15 at the targeted allele, and enabling direct visualization and genetic modification of Gdf15-expressing cells. We extensively mapped Gdf15 expression in the normal kidney and following bilateral ischemia-reperfusion injury, and quantified and compared renal responses to ischemia-reperfusion injury in the presence and absence of GDF15. In addition, we analyzed single nucleotide polymorphism association data for GDF15 for associations with patient kidney transplant outcomes.ResultsGdf15 is normally expressed within aquaporin 1–positive cells of the S3 segment of the proximal tubule, aquaporin 1–negative cells of the thin descending limb of the loop of Henle, and principal cells of the collecting system. Gdf15 is rapidly upregulated within a few hours of bilateral ischemia-reperfusion injury at these sites and new sites of proximal tubule injury. Deficiency of Gdf15 exacerbated acute tubular injury and enhanced inflammatory responses. Analysis of clinical transplantation data linked low circulating levels of GDF15 to an increased incidence of biopsy-proven acute rejection.ConclusionsGdf15 contributes to an early acting, renoprotective injury response, modifying immune cell actions. The data support further investigation in clinical model systems of the potential benefit from GDF15 administration in situations in which some level of tubular injury is inevitable, such as following a kidney transplant.

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Section: Discussionmentioning

confidence: 85%

Renoprotective and Immunomodulatory Effects of GDF15 following AKI Invoked by Ischemia-Reperfusion Injury

Liu

Kumar

Heinzel

et al. 2020

JASN

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“…It is consistent in pre-eclampsia patients (34). RNA-seq data of wildtype (WT) mice treated by a high salt diet showed a significant upregulation of heat-shock proteins Hspa1b (Hsp70) and blood pressure that were both abolished in UMOD knockout mice (35)(36)(37). It indicated the potential causal relationship between UMOD and hypertension, but was difficult to confirm in a population study.…”

Section: Discussionmentioning

confidence: 93%

High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study

You,

Chen,

et al. 2021

Journal of the American Society of Nephrology

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Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure. Methods:We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension ("ukb-b-14057" and "ukb-b-14177") is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in "ieu-b-38" and "ukb-b-20175", respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in "ieu-b-39" and 0.05 (SE = 0.01, P = 2.13E-10) in "ukb-b-7992". As for the sUMOD, the OR of hypertension ("ukb-b-14057" and "ukb-b-14177") is 1.01 (95% CI 1.01-1.02, all P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in "ieu-b-38" and 0.01 (SE = 0.003, P = 1.04E-04) in "ukb-b-20175". The sUMOD is causally associated with elevated DBP ("ieu-b-39": β = 0.313, SE = 0.050, P = 3.43E-10; "ukb-b-7992": β = 0.018, SE = 0.003, P = 8.41E-09). Conclusion:Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

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“…HSPA1B and HSPA2 , also known as HSP70-1/1B and HSP70-2/3, locate on chromosome 6p21.33 and 14q23.3, respectively; both of them encode for the classical Hsp70s proteins. HSPA1B was adaptively increased under salt stress in renal tubular and osmotic stress in collecting duct cells of rodents ( 39 , 40 ). HSPA2 has prominent roles in the morphological differentiation of male germ cells as well as their functional transformation during post-testicular sperm maturation ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

Wang

Hao

et al. 2022

Front. Endocrinol.

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Pyruvate kinase M2 (PKM2), as the terminal and last rate-limiting enzyme of the glycolytic pathway, is an ideal enzyme for regulating metabolic phenotype. PKM2 tetramer activation has shown a protective role against diabetic kidney disease (DKD). However, the molecular mechanisms involved in diabetic tubular have not been investigated so far. In this study, we performed transcriptome gene expression profiling in human renal proximal tubular epithelial cell line (HK-2 cells) treated with 25 mM high D-glucose (HG) for 7 days before the addition of 10 μM TEPP-46, an activator of PKM2 tetramerization, for a further 1 day in the presence of HG. Afterwards, we analyzed the differentially expressed (DE) genes and investigated gene relationships based on weighted gene co-expression network analysis. The results showed that 2,902 DE genes were identified (adjusted P-value ≤ 0.05), where 2,509 DE genes (86.46%) were co-expressed in the key module. Four extremely downregulated DE genes (HSPA8, HSPA2, HSPA1B, and ARRB1) and three extremely upregulated DE genes (GADD45A, IGFBP3, and SIAH1) enriched in the downregulated endocytosis (hsa04144) and upregulated p53 signaling pathway (hsa04115), respectively, were validated by qRT-PCR experiments. The qRT-PCR results showed that the relative expression levels of HSPA8 [adjusted P-value = 4.45 × 10-34 and log2(FC) = -1.12], HSPA2 [adjusted P-value = 6.09 × 10-14 and log2(FC) = -1.27], HSPA1B [adjusted P-value = 1.14 × 10-11 and log2(FC) = -1.02], and ARRB1 [adjusted P-value = 2.60 × 10-5 and log2(FC) = -1.13] were significantly different (P-value < 0.05) from the case group to the control group. Furthermore, the interactions and predicted microRNAs of the key genes (HSPA8, HSPA2, HSPA1B, and ARRB1) were visualized in networks. This study identified the key candidate transcriptomic biomarkers and biological pathways in hyperglycemic HK-2 cells responding to the PKM2 activator TEPP-46 that can highlight a possibility of PKM2 tetramerization reshaping the interplay among endocytic trafficking through the versatile networks of Hsp70s and rewiring the crosstalk between EGFR signal transduction circuits and metabolic stress to promote resilience, which will be valuable for further research on PKM2 in DKD.

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Salt stress in the renal tubules is linked to TAL-specific expression of uromodulin and an upregulation of heat shock genes

Cited by 8 publications

References 52 publications

Renoprotective and Immunomodulatory Effects of GDF15 following AKI Invoked by Ischemia-Reperfusion Injury

Renoprotective and Immunomodulatory Effects of GDF15 following AKI Invoked by Ischemia-Reperfusion Injury

High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study

Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

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