Prevention of hypertension-induced renal vascular dysfunction through a p66Shc-targeted mechanism

Renal microvascular injury occurs in most patients with hypertension-induced nephropathy (HN). We have shown that overexpression of adaptor protein p66Shc is implicated in the loss of renal microvascular reactivity in hypertensive rats. Since sulfur heteroarotinoid A2 (SHetA2) modulates p66Shc, we tested whether SHetA2 would restore renal microvascular reactivity and mitigate kidney injury in a rat HN model. Dahl salt sensitive (SS) and p66Shc knockout (p66Shc-KO) rats were used in a well-established rat model of HN, characterized by severe renal vascular dysfunction. SHetA2 was either added acutely to isolated rat afferent arterioles or chronically administrated to rats during HN development. The ability of SHetA2 treatment to restore afferent arteriolar contraction in response to increased perfusion pressure or ATP was evaluated using the perfused juxtamedullary nephron preparation. The progression of renal damage was evaluated by measuring urinary protein excretion and conducting analysis of glomerular injury. Comparison of renal microvascular responses to perfusion pressure in p66Shc-KO rats and parental SS rats, in the presence and absence of acute preincubation with SHetA2, revealed a dose-dependent ability of SHetA2 to restore renal microvascular reactivity in SS rats with little effect upon p66Shc knockouts. Moreover, chronic treatment with SHetA2 prevented loss of renal microvascular responses and decline in renal function. SHetA2 was more potent and effective in males compared with females. Targeting p66Shc with SHetA2 diminishes renal damage and restores renal afferent arteriolar reactivity caused by hypertension. These results justify further translation of these findings to develop SHetA2 for prevention and treatment of hypertension-induced kidney damage.<b>NEW & NOTEWORTHY</b> Acute preincubation with modulator of p66Shc signaling sulfur heteroarotinoid A2 (SHetA2) revealed dose-dependent ability of SHetA2 to restore renal microvascular reactivity in rats with hypertension-induced nephropathy. Moreover, chronic treatment with SHetA2 prevented loss of renal microvascular responses and decline in renal function. Thus, targeting p66Shc with SHetA2 diminishes renal damage and restores renal afferent arteriolar reactivity caused by hypertension.