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Abstract: PO2141

A Novel Genetically Defined Mouse Model of Hypertensive Nephropathy

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Tatomir, Anamaria, Johns Hopkins University, Baltimore, Maryland, United States
  • Jung, Hyun Jun, Johns Hopkins University, Baltimore, Maryland, United States
  • Daneshpajouhnejad, Parnaz, Johns Hopkins University, Baltimore, Maryland, United States
  • Rosenberg, Avi Z., Johns Hopkins University, Baltimore, Maryland, United States
  • Delpire, Eric J., Vanderbilt University, Nashville, Tennessee, United States
  • Welling, Paul A., Johns Hopkins University, Baltimore, Maryland, United States
  • Grimm, Paul Richard, Johns Hopkins University, Baltimore, Maryland, United States
Background

The molecular pathways that drive hypertensive nephropathy remain poorly understood. We overcome the roadblock with a new genetically-defined mouse model of HTN that exhibit a low-renin salt-sensitive form of the disease. The mice, created by introducing activating mutations in the Ste20p-related proline alanine-rich kinase (SPAK) in a distal convoluted tubule cell-specific manner, become hypertensive solely as a consequence of constitutive activation of the thiazide-sensitive sodium chloride cotransporter (NCC) and salt retention.

Methods

For these studies, the constitutively active (CA)-SPAK and control (C57BL/6J) mice were fed control or high salt diet (HSD), and renal function was evaluated over 40 weeks, together with telemetric measurements of blood pressure. RNA-Seq was performed to evaluate changes in the transcriptional profile in the renal cortex and corroborated biochemically.

Results

Kidney function in the CA-SPAK mice began to deteriorate at 20 weeks as evidenced by significant elevation of BUN, creatinine, and frank albuminuria, which gradually increased over the next 20 weeks. HSD consumption exacerbated hypertension in CA-SPAK mice and accelerated the decline in renal function. Trichrome-staining revealed no obvious histopathological changes, including nephroangiosclerosis.
By contrast, a significant change in the transcription profile was observed between CA-SPAK mice and controls at an early stage when microalbuminuria begins to develop. Remarkably, the differentially expressed (DE) genes profile was enriched in 26% of the known genes associated with albuminuria in humans. Significant downregulation of key components of the glomerular filtration barrier slit diaphragm genes (nephrin, podocalyxin, synaptopodin) and the proximal tubule protein scavenger, Cubilin, were also observed in the CA-SPAK. Pathway analysis was especially enriched for genes associated with Major Histocompatibility Complex class II, T helper 17 lymphocytes and B lymphocytes markers in the CA-SPAK mice.

Conclusion

Progression of renal insufficiency in CA-SPAK mice indicates a causal role of hypertension in nephropathy and incriminates an inflammatory component as a key driver of early damage to the glomerular filtration barrier and tubular protein reabsorption.