A Novel Genetically Defined Mouse Model of Hypertensive Nephropathy
Authors: Tatomir Anamaria , Jung Hyun Jun , Delpire Eric , Welling Paul A. , Grimm P. Richard 
Published: April 2020

The molecular pathways that drive hypertensive nephropathy remain poorly understood. Hypertension (HTN) and chronic kidney disease are comorbid disorders with a correlation as high as 70% in African‐Americans over 65 years old. Because impaired kidney function can be the cause or consequence of HTN, identification of causal hypertensive nephropathy pathways has been especially difficult. Here, we overcome the roadblock with a new genetically‐defined mouse model of HTN that exhibit a low‐renin salt‐sensitive form of the disease, similar to HTN in individuals of sub‐Saharan African descent. 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.

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.

Renal function in 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. Microscopic evaluation of trichrome‐stained specimens revealed no significant changes in the kidney parenchyma. Thus hypertension appears to drive kidney insufficiency long before the development of 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. 1905 differentially expressed (DE) genes were identified (modified TREAT method, FDR < 0.05 for genes > 10% change). Remarkably, the DE profile was enriched in 26% of the known genes associated with albuminuria in humans (Chi Square test, p = 0.00031). Significant downregulation of key components of the glomerular filtration barrier slit diaphragm genes (nephrin, podocalyxin, synaptopodin, actinin a4, phospholipase C ɛ1) and the proximal tubule protein scavenger, Cubilin, were also observed in the CA‐SPAK. Pathway analysis was especially enriched in proinflammatory responses. Signature genes associated with Major Histocompatibility Complex class II, T helper 17 lymphocytes master regulator transcription factors and B lymphocytes markers were up‐regulated in the CA‐SPAK mice.

In 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.

Support or Funding Information

This study was supported by NIH.